Compounds

ABSTRACT

The invention provides compounds of general formula 
                 
 
wherein R 1 , m, Q, T, n, R 2 , R 3 , V, W, X and R 4  are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

CROSS REFERENCE TO RELATED CASES

This application is a continuation application of, and claims priorityfrom, U.S. patent application Ser. No., 09/555,565, filed Jun. 1, 2000now U.S. Pat. No. 6,518,286, which claims priority from PCT ApplicationNo. PCT/SE00/00563, filed Mar. 22, 2000, which claims priority from bothSwedish Application No. 99011173, filed Mar. 26, 1999 and SwedishApplication No. 99021941, filed Jun. 10, 1999. Each of the aboveapplications is hereby incorporated by reference in its entirety.

The present invention relates to novel compounds, processes for theirpreparation, pharmaceutical compositions containing them and their usein therapy.

Chemokines play an important role in immune and inflammatory responsesin various diseases and disorders, including asthma and allergicdiseases, as well as autoimmune pathologies such as rheumatoid arthritisand atherosclerosis. These small secreted molecules are a growingsuperfamily of 8-14 kDa proteins characterised by a conserved fourcysteine motif. The chemokine superfamily can be divided into two maingroups exhibiting characteristic structural motifs, the Cys-X-Cys(C-X-C) and Cys-Cys (C-C) families. These are distinguished on the basisof a single amino acid insertion between the NH-proximal pair ofcysteine residues and sequence similarity.

The C-X-C chemokines include several potent chemoattractants andactivators of neutrophils such as interleukin-8 (IL-8) andneutrophil-activating peptide 2 (NAP-2).

The C-C chemokines include potent chemoattractants of monocytes andlymphocytes but not neutrophils such as human monocyte chemotacticproteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation,Normal T Expressed and Secreted), eotaxin and the macrophageinflammatory proteins 1α and 1β (MIP-1α and MIP-1β).

Studies have demonstrated that the actions of the chemokines aremediated by subfamilies of G protein-coupled receptors, among which arethe receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. Thesereceptors represent good targets for drug development since agents whichmodulate these receptors would be useful in the treatment of disordersand diseases such as those mentioned above.

Certain piperidinyl derivatives and piperazinyl derivatives are knownfrom U.S. Pat. Nos. 3,787,419, 4,559,349 and 5,210,086 for userespectively as central nervous system depressants, antipsychotic agentsand as α₁-adrenoreceptor antagonists.

In accordance with the present invention, there is therefore provided acompound of general formula

wherein:

-   R¹ represents a C₁-C₁₂ alkyl group optionally substituted by one or    more substituents independently selected from cyano, hydroxyl, C₁-C₆    alkoxy, C₁-C₆ alkylthio and C₁-C₆ alkoxycarbonyl groups, or-   R¹ represents a 3- to 10-membered saturated or unsaturated ring    system which may comprise up to two ring carbon atoms that form    carbonyl groups and which may comprise up to 4 ring heteroatoms    independently selected from nitrogen, oxygen and sulfur, the ring    system being optionally substituted by one or more substituents    independently selected from halogen atoms, and cyano, nitro,    hydroxyl, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆    alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —NR⁵R⁶, C₃-C₆    cycloalkylamino, C₁-C₆ alkylthio, C₁-C₆ alkylthioC₁-C₆ alkyl, C₁-C₆    alkylcarbonylamino, —C(O)NR⁷R⁸, sulphonamido (—SO₂NH₂), (di)C₁-C₆    alkylsulphonamido, phenyl, phenylamino, nitrophenyl, pyridyl,    pyridylthio, benzodioxanyl, thienyl, furanyl, and C(O)R⁹-substituted    C₁-C₆ alkyl or C₁-C₆ alkoxy groups;-   m is 0 or 1;-   Q represents a group OCH₂, C₁-C₄ alkylene or C₂-C₄ alkenylene;-   T represents a group C(O)NH, or when m is 0, T may additionally    represent a bond or a group NH, or when m is 1 and Q represents    C₁-C₄ alkylene, T may additionally represent a group NH;-   n is 1, 2, 3 or 4;-   each R² independently represents a hydrogen atom or a C₁-C₄ alkyl    group;-   each R³ independently represents a hydrogen atom or a C₁-C₄ alkyl    group;-   V represents a nitrogen atom;-   W represents a nitrogen atom or a group CH;-   X represents an oxygen atom or a group C(O), CH(OH), NH or N(C₁-C₆    alkyl), provided that when W represents a nitrogen atom, then X    represents C(O);-   R⁴ represents a phenyl group optionally substituted by one or more    substituents independently selected from halogen atoms, and amino,    nitro, cyano, sulphonyl (—SO₃H), sulphonamido (—SO₂NH₂), C₁-C₆    alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy and C₁-C₆ alkylsulphonyl    groups;-   R⁵ and R⁶ each independently represent a hydrogen atom or a C₁-C₆    alkyl or hydroxyC₁-C₆ alkyl group, or R⁵ and R⁶ together with the    nitrogen atom to which they are attached form a 4- to 7-membered    saturated heterocyclic ring;-   R⁷ and R⁸ each independently represent a hydrogen atom or a C₁-C₆    alkyl group; and-   R⁹ represents a hydroxyl or —NR⁷R⁸ group;-   with the provisos that-   (a) when m is 0, T is CONH, n is 2, 3 or 4 and each R² and R³    represents hydrogen, W is CH, X is C(O) or CH(OH) and R¹ represents    a substituted 3- to 10-membered unsaturated ring system, then the    one or more substituents in the ring system do not include hydroxyl,    halogen, C₁-C₆ alkoxy or C₁-C₆ haloalkoxy, and-   (b) when W is N, X is C(O), R⁴ represents 3-trifluoromethylphenyl, m    is 0 and T is a bond, then R¹ and (CR²R³)_(n) taken together do not    represent a C₁-C₆ alkyl group, and-   (c) when W is CH, X is O, n is 2 or 3 and each R² and R³ represents    hydrogen, m is 0 and T is NH, then R¹ does not represent a group    or a pharmaceutically acceptable salt or solvate thereof.

In the context of the present specification, an alkyl substituent groupor an alkyl moiety in a substituent group may be linear or branched.Further, the alkyl moieties in a dialkylamino, di(hydroxyalkyl)amino ordialkylsulphonamido substituent group may be the same or different.

R¹ represents a C₁-C₁₂, preferably C₁-C₁₀, alkyl group optionallysubstituted by one or more (e.g. one, two, three or four) substituentsindependently selected from cyano, hydroxyl, C₁-C₆, preferably C₁-C₄,alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy),C₁-C₆, preferably C₁-C₄, alkylthio (e.g. methyl-, ethyl-, propyl-,butyl-, pentyl- or hexylthio) and C₁-C₆, preferably C₁-C₄,alkoxycarbonyl (e.g. methoxy-, ethoxy-, propoxy-, butoxy-, pentoxy- orhexoxycarbonyl) groups, or R¹ represents a 3- to 10-membered saturatedor unsaturated ring system comprising up to two ring carbon atoms thatform carbonyl groups and comprising up to 4 ring heteroatomsindependently selected from nitrogen, oxygen and sulfur, the ring systembeing optionally substituted by one or more (e.g. one, two, three orfour) substituents independently selected from halogen atoms (fluorine,chlorine, bromine or iodine), and cyano, nitro, hydroxyl, C₁-C₆ alkyl(e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,pentyl or hexyl), C₃-C₆ cycloalkyl (cyclopropyl, cyclobutyl, cyclopentylor cyclohexyl), C₁-C₆ alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy,pentoxy or hexoxy), C₁-C₆ alkoxycarbonyl (e.g. methoxy-, ethoxy-,propoxy-, butoxy-, pentoxy- or hexoxycarbonyl), C₁-C₆ haloalkyl (e.g.trifluoromethyl), C₁-C₆ haloalkoxy (e.g. trifluoromethoxy), —NR⁵R⁶,C₃-C₆ cycloalkylamino (cyclopropyl-, cyclobutyl-, cyclopentyl- orcyclohexylamino), C₁-C₆ alkylthio (e.g. methyl-, ethyl-, propyl-,butyl-, pentyl- or hexylthio), C₁-C₆ alkylthioC₁-C₆ alkyl (e.g.methylthiomethyl), C₁-C₆ alkylcarbonylamino (e.g. methyl-, ethyl-,propyl-, butyl-, pentyl- or hexylcarbonylamino), —C(O)NR R⁷R⁸,sulphonamido (—SO₂NH₂), (di)C₁-C₆ alkylsulphonamido (e.g.(di)methylsulphonamido or (di)ethylsulphonamido), phenyl, phenylamino,nitrophenyl, pyridyl, pyridylthio, benzodioxanyl, thienyl, furanyl, andC(O)R⁹-substituted C₁-C₆ alkyl or C₁-C₆ alkoxy groups, the alkyl andalkoxy moieties being as defined above.

The 3- to 10-membered saturated or unsaturated ring system in the groupR¹ may be monocyclic, or polycyclic comprising 2 or more fused rings,examples of which include cyclobutyl, cyclopentyl, cyclohexyl,norbornylenyl, adamantyl, piperidyl, phenyl, naphthyl, naphthyridinyl,1,3-benzodioxolyl, pyrazolyl, furanyl, pyridyl, thienyl, benzoxazolyl,benzothiazolyl, chromonyl, imidazolyl, quinolinyl, isoquinolinyl,benzimidazolyl, pyrimidinyl, pyrazolopyrimidinyl, thienopyrimidinyl,thiazolopyrimidinyl, pyrimidinedione, pyrazinyl, pyridazinyl, purinyl,quinoxalinyl, thiazolyl, isothiazolyl and2,4-dioxo-3,4-dihydro-quinazolinyl.

Preferably, R¹ represents a C₁-C₁₀ alkyl group optionally substituted byone or two substituents independently selected from cyano, hydroxyl,C₁-C₄ alkoxy, C₁-C₄ alkylthio and C₁-C₄ alkoxycarbonyl groups, or R¹represents a 3- to 10-membered saturated or unsaturated ring systemcomprising up to two ring carbon atoms that form carbonyl groups andcomprising up to 4 ring heteroatoms independently selected fromnitrogen, oxygen and sulfur, the ring system being optionallysubstituted by one, two or three substituents independently selectedfrom halogen atoms, and cyano, nitro, hydroxyl, C₁-C₄ alkyl, C₃-C₆cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxycarbonyl, C₁-C₃ haloalkyl, C₁-C₃haloalkoxy, —NR⁵R⁶, C₃-C₆ cycloalkylamino, C₁-C₄ alkylthio, C₁-C₄alkylthioC₁-C₄ alkyl, C₁-C₄ alkylcarbonylamino, —C(O)NR⁷R⁸, phenyl,phenylamino, nitrophenyl, pyridyl, pyridylthio, benzodioxanyl, thienyl,furanyl, and C(O)R⁹-substituted C₁-C₄ alkyl or C₁-C₄ alkoxy groups.

Preferably Q represents a group OCH₂, C₁-C₃ alkylene or C₂-C₃alkenylene.

Each R² independently represents a hydrogen atom or a C₁-C₄ alkyl (e.g.methyl, ethyl, propyl, isopropyl or butyl) group, and is especially ahydrogen atom.

Each R³ independently represents a hydrogen atom or a C₁-C₄ alkyl (e.g.methyl, ethyl, propyl, isopropyl or butyl) group, and is especially ahydrogen atom.

Preferably n is 2 or 3.

X preferably represents an oxygen atom or a group C(O) or NH.

R⁴ represents a phenyl group optionally substituted by one or more (e.g.one, two, three or four) substituents independently selected fromhalogen atoms (fluorine, cholorine, bronine or iodine), and amino,nitro, cyano, sulphonyl (—SO₃H), sulphonamido (—SO₂NH₂), C₁-C₆,preferably C₁-C₄, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl orhexyl), C₁-C₆, preferably C₁-C₄, haloalkyl (e.g. trifluoromethyl),C₁-C₆, preferably C₁-C₄, haloalkoxy (e.g. trifluoromethoxy) and C₁-C₆,preferably C₁-C₄, alkylsulphonyl (e.g. methyl-, ethyl-, propyl-, butyl-,pentyl- or hexylsulphonyl) groups.

Preferably, R⁴ represents a phenyl group optionally substituted by oneor two halogen atoms, particularly chlorine atoms.

R⁵ and R⁶ each independently represent a hydrogen atom or a C₁-C₆,preferably C₁-C₄, alkyl or hydroxyC₁-C₆, preferably C₁-C₄, alkyl group,or R⁵ and R⁶ together with the nitrogen atom to which they are attachedform a 4- to 7-membered saturated heterocyclic ring. The alkyl moiety ineach case may, for example, be a methyl, ethyl, propyl, butyl, pentyl orhexyl group. In the hydroxyalkyl group, the hydroxyl group may beattached to any suitable carbon atom of the alkyl moiety.

R⁷ and R⁸ each independently represent a hydrogen atom or a C₁-C₆,preferably C₁-C₄, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl orhexyl) group. Preferably, R⁷ and R⁸ each independently represent ahydrogen atom or a methyl group.

R⁹ represents a hydroxyl or, preferably, —NR⁵R⁶ group.

Examples of particularly preferred compounds of the invention include:

-   4-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-2-[2-(dimethylamino)-2-oxoethoxy]benzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-ethoxybenzamide    hydrochloride,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-isopropoxybenzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-ethoxybenzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-(trifluoromethoxy)benzamide    hydrochloride,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-methoxybenzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-(trifluoromethoxy)benzamide    hydrochloride,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-furamide    hydrochloride,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-phenylacetamnide    hydrochloride,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-methoxybenzamide    hydrochloride,-   3-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide    hydrochloride,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-fluorobenzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-fluorobenzamide    hydrochloride,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-hydroxybenzamide    hydrochloride,-   N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-[2-(methylamino)-2-oxoethoxy]benzamide    hydrochloride,-   2-[3-{2-[4-(4-Fluorobenzoyl)-1-piperidinyl]ethyl}-2,4-dioxo-3,4-dihydro-1(2H)-quinazolinyl]-N,N-dimethylacetamide    hydrochloride,-   N-{2-[4-(3,4-Dichlorobenzoyl)-1-piperazinyl]ethyl}-3-methoxybenzamide    hydrochloride,-   3,4-Dichloro-N-{2-[4-(3,4-dichlorobenzoyl)-1-piperazinyl]ethyl}benzamide,-   4-Chloro-N-{2-[4-(3,4-dichlorobenzoyl)-1-piperazinyl]ethyl}-2-[2-(dimethylamino)-2-oxoethoxy]benzamide    hydrochloride,

N˜7˜-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-5-methyl[1,3]thiazolo[4,5-d]pyrimidine-2,7-diamine,

-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-9-methyl-9H-purin-6-amine,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-1,3-benzothiazol-2-amine,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-1,3-benzoxazol-2-amine,-   6-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-2-pyrazinamine,-   6-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-3-pyridazinamine,-   6-({2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}amino)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione,-   N-{1-[4-(3,4-Dichlorophenoxy)-piperidin-1-ylmethyl]-2-methyl-propyl}-4-methyl-benzamide,    hydrochloride salt,-   N-{1-[4-(3,4-Dichloro-phenoxy)-piperidin-1-ylmethyl]-2-methyl-propyl}-3-methoxy-benzamide,    hydrochloride salt,-   N-{2-[4-(3,4-Dichloroanilino)-1-piperidinyl]ethyl}-3-methoxybenzamide    dihydrochloride,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-N-(3-methoxybenzyl)amine    dihydrochloride,-   3-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-6-methoxy-2,4(1H,3H)-quinazolinedione,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-fluorobenzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,-   4-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-methoxybenzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-methoxybenzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-methoxybenzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-nitrobenzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-methylbenzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-(trifluoromethyl)benzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3,5-dinitrobenzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-iodobenzamide,-   4-Cyano-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,-   4-Bromo-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-methylbenzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-nitrobenzamide,-   3-Bromo-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,-   3,4-Dichloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-fluorobenzamide,-   2,4-Dichloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-methylbenzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-iodobenzamide,-   4-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-3-nitrobenzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-methyl-3-nitrobenzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-fluoro-5-(trifluoromethyl)benzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-(trifluoromethoxy)benzamide,-   3,5-Dichloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-(trifluoromethyl)benzamide,-   3-Cyano-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,-   2-Bromo-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-5-methoxybenzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-furamide,-   3-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,-   2-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3,5-difluorobenzamide,-   2,3-Dichloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-naphthamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(methylsulfanyl)nicotinamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-fluoro-6-(trifluoromethyl)benzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2,4-difluorobenzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-thiophenecarboxamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-quinoxalinecarboxamide,-   Methyl    4-({2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}amino)-4-oxobutanoate,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}bicyclo[2.2.1]hept-5-ene-2-carboxamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}cyclobutanecarboxamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-methoxyacetamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}cyclohexanecarboxamide,-   (E)-N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-phenyl-2-propenamide,-   2-Chloro-N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}nicotinamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-phenylacetamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}cyclopentanecarboxamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-phenoxyacetamide,-   N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}benzamide,-   N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-(trifluoromethyl)benzamide,-   4-(tert-Butyl)-N-{2-[4-(4-chlorobenzoyl)-1-piperidinyl]ethyl}benzamide,-   N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-4-methylbenzamide,-   N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-4-nitrobenzamide,-   N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-methylbenzamide,-   N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-4-methyl-3-nitrobenzamide,-   N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-cyanobenzamide,-   N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-furamide,-   N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-nitrobenzamide,-   N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-naphthamide,-   N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-(methylsulfanyl)nicotinamide,-   N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-(2,3-dihydro-1,4-benzodioxin-2-yl)-1,3-thiazole-4-carboxamide,-   N˜2˜-Cyclopropyl-N˜4˜-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-2,4-pyrimidinediamine,-   2-{[4-({2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}amino)-2-pyrimidinyl]amino}-1-ethanol,-   2-[[4-({2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}amino)-2-pyrimidinyl](methyl)amino]-1-ethanol,-   N˜4˜-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-N˜2˜-phenyl-2,4-pyrimidinediamine,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(methylsulfanyl)-4-pyrimidinamine-   N˜4˜-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-6-methyl-2,4-pyrimidinamine,-   N˜4˜-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-N˜2˜,6-dimethyl-2,4-pyrimidinediamine,-   2-Chloro-N˜4˜-cyclopropyl-N˜6˜-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-4,6-pyrimidinediamine,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-phenyl-2-pyrimidinamine,-   N˜2˜-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-N˜4˜,N˜4˜,6-trimethyl-2,4-pyrimidinediamine,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-(trifluoromethyl)-2-pyrimidinamine,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-(propylsulfanyl)-2-pyrimidinamine,-   N˜2˜-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-N˜4˜-phenyl-2,4-pyrimidinediamine,-   N˜4˜-Cyclopropyl-N˜2˜-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-2,4-pyrimidinediamine,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}[1,8]naphthyridin-2-amine,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-(3-pyridinyl)-2-pyrimidinamine,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-pyrimidinamine,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4,6-dimethoxy-2-pyrimidinamine,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-(3-furyl)-2-pyrimidinamine,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-1H-purin-6-amine,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-5-methylthieno[2,3-d]pyrimidin-4-amine,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-7-methylthieno[3,2-d]pyrimidin-4-amine,-   N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-thiophenecarboxamide,-   N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-quinoxalinecarboxamide,-   N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}bicyclo[2.2.1]hept-5-ene-2-carboxamide,-   N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}cyclohexanecarboxamide,-   (E)-N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-phenyl-2-propenamide,-   N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-phenoxyacetamide,-   (E)-N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-(4-nitrophenyl)-2-propenamide,-   2-(1-Adamantyl)-N-{2-[4-(4-chlorobenzoyl)-1-piperidinyl]ethyl}acetamide,-   (4-Chlorophenyl)(1-{2-[(2-fluoro-4,5-dimethoxybenzyl)amino]ethyl}-4-piperidinyl)methanone,-   (4-Chlorophenyl)(1-{2-[(3,4,5-trimethoxybenzyl)amino]ethyl}-4-piperidinyl)methanone,-   (4-Chlorophenyl)(1-{2-[(3-nitrobenzyl)amino]ethyl}-4-piperidinyl)methanone,-   (4-Chlorophenyl){1-[2-(isobutylamino)ethyl]-4-piperidinyl}methanone,-   4-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}amino)methyl]-4-ethylhexanenitrile,-   (4-Chlorophenyl)(1-{2-[(7-hydroxy-3,7-dimethyloctyl)amino]ethyl}-4-piperidinyl)methanone,-   (4-Chlorophenyl)[1-(2-{[(6-nitro-1,3-benzodioxol-5-yl)methyl]amino}ethyl)-4-piperidinyl]methanone,-   [1-(2-{[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl]amino}ethyl)-4-piperidinyl](4-chlorophenyl)methanone,-   (4-Chlorophenyl)[1-(2-{[3-nitro-4-(2-pyridinylsulfanyl)benzyl]amino}ethyl)-4-piperidinyl]methanone,-   (4-Chlorophenyl)[1-(2-{[(E)-3-(4-nitrophenyl)-2-propenyl]amino}ethyl)-4-piperidinyl]methanone,-   (4-Chlorophenyl){1-[2-({[5-(3-nitrophenyl)-2-furyl]methyl}amino)ethyl]-4-piperidinyl}methanone,-   (4-Chlorophenyl)[1-(2-{[5-nitro-2-(2-pyridinylsulfanyl)benzyl]amino}ethyl)-4-piperidinyl]methanone,-   6-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}amino)methyl]-2-(methylsulfanyl)nicotinonitrile,-   {1-[2-({[5-Chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}amino)ethyl]-4-piperidinyl}(4-chlorophenyl)methanone,-   (4-Chlorophenyl)[1-(2-{[3-(methylsulfanyl)butyl]amino}ethyl)-4-piperidinyl]methanone,-   (4-Chlorophenyl)[1-(2-{[(4-phenyl-4-piperidinyl)methyl]amino}ethyl)-4-piperidinyl]methanone,-   (4-Chlorophenyl)[1-(2-{[(1-phenyl-1H-pyrazol-5-yl)methyl]amino}ethyl)-4-piperidinyl]methanone,-   Ethyl    3-[({2-[4-(4-chlorobenzoyl)-1-piperidinyl]ethyl}-amino)methyl]cyclohexanecarboxylate,-   N-{4-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}amino)methyl]phenyl}acetamide,-   (4-Chlorophenyl)(1-{2-[(2,5-dichlorobenzyl)amino]ethyl}-4-piperidinyl)methanone,-   (4-Chlorophenyl)(1-{2-[(4-nitrobenzyl)amino]ethyl}-4-piperidinyl)methanone,-   (4-Chlorophenyl)(1-{2-[(2,6-dichlorobenzyl)amino]ethyl}-4-piperidinyl)methanone,-   (4-Chlorophenyl)(1-{2-[(2-pyridinylmethyl)amino]ethyl}-4-piperidinyl)methanone,-   (4-Chlorophenyl)[1-(2-{[(3-methyl-2-thienyl)methyl]amino}ethyl)-4-piperidinyl]methanone,-   (4-Chlorophenyl)(1-{2-[(3-hydroxy-4-methoxybenzyl)amino]ethyl}-4-piperidinyl)methanone,-   3-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}amino)methyl]-4H-chromen-4-one,-   [1-(2-{[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl]amino}ethyl)-4-piperidinyl](4-chlorophenyl)methanone,-   (4-Chlorophenyl)[1-(2-{[(2,6-dichloro-4-pyridinyl)methyl]amino}ethyl)-4-piperidinyl]methanone,-   (4-Chlorophenyl)[1-(2-{[(2-phenyl-1H-imidazol-4-yl)methyl]amino}ethyl)-4-piperidinyl]methanone,-   (4-Chlorophenyl)[1-(2-{[(5-ethyl-2-thienyl)methyl]amino}ethyl)-4-piperidinyl]methanone,-   (4-Chlorophenyl)[1-(2-{[(2-chloro-3-quinolinyl)methyl]amino}ethyl)-4-piperidinyl]methanone,-   (4-Chlorophenyl)[1-(2-{[(6-methyl-2-pyridinyl)methyl]amino}ethyl)-4-piperidinyl]methanone,-   (4-Chlorophenyl)(1-{2-[(3-quinolinylmethyl)amino]ethyl}-4-piperidinyl)methanone,-   4-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}amino)methyl]-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one,-   (4-Chlorophenyl)(1-{2-[(4-pyridinylmethyl)amino]ethyl}-4-piperidinyl)methanone,-   (4-Chlorophenyl)(1-{2-[(3-hydroxy-4-nitrobenzyl)amino]ethyl}-4-piperidinyl)methanone,-   (4-Chlorophenyl)(1-{2-[(3,5-difluorobenzyl)amino]ethyl}-4-piperidinyl)methanone,-   (1-{2-[(2-Chloro-6-fluorobenzyl)amino]ethyl}-4-piperidinyl)(4-chlorophenyl)methanone,-   [1-(2-{[(4-Bromo-1H-pyrazol-3-yl)methyl]amino}ethyl)-4-piperidinyl](4-chlorophenyl)methanone,-   3-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}amino)methyl]-6,7-dimethyl-4H-chromen-4-one,-   2-{2-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}amino)methyl]-4-nitrophenoxy}acetic    acid,-   (4-Chlorophenyl)[1-(2-{[(1-methyl-1H-benzimidazol-2-yl)methyl]amino}ethyl)-4-piperidinyl]methanone,-   (4-Chlorophenyl)[1-(2-{[(2,4-dimethoxy-5-pyrimidinyl)methyl]amino}ethyl)-4-piperidinyl]methanone,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-(methylamino)benzamide,-   4-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-3-methoxybenzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-methoxy-4-methylbenzamide,-   3-Amino-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-4-methoxybenzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-1,3-benzodioxole-5-carboxamide,-   4-Amino-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-3-methoxybenzamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-fluoro-4-methoxybenzamide,-   5-Bromo-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-2-furamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-methyl-2-furamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4,5-dimethyl-2-furamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-7-ethoxy-1-benzofuran-2-carboxamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-5-methoxy-1-benzofuran-2-carboxamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-7-methoxy-1-benzofuran-2-carboxamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(4-fluorophenyl)acetamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(2-methoxyphenyl)acetamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(3-methylphenyl)acetamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(2-methylphenyl)acetamide,-   2-(3-Bromophenyl)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}acetamide,-   2-(2-Chlorophenyl)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}acetamide,-   2-(4-Chlorophenyl)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}acetamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-[2-(trifluoromethyl)phenyl]acetamide,-   2-(3-Chlorophenyl)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}acetamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(3,4-dimethoxyphenyl)acetamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(4-methoxyphenyl)acetamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(3,4-dichlorophenyl)acetamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(3-fluoro-4-methoxyphenyl)acetamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(4-ethoxyphenyl)acetamide,-   2-(1,3-Benzodioxol-5-yl)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}acetamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-[4-(dimethylamino)phenyl]acetamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(4-methylphenyl)acetamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(3,4-difluorophenyl)acetamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(3-methoxyphenyl)acetamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-phenylbutanamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-phenylpropanamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-(3-methoxyphenyl)propanamide,-   2-Amino-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-1,3-thiazole-4-carboxamide,-   2-(Acetylamino)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-1,3-thiazole-4-carboxamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(4-pyridinyl)-1,3thiazole-4-carboxamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2,4-dimethyl-1,3-thiazole-5-carboxamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2,5-dimethyl-1,3-oxazole-4-carboxamide,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-1H-imidazole-4-carboxamide,-   N-{2-[4-(3,4-Chlorophenoxy)-1-piperidinyl]ethyl}-3-methoxybenzamide,    hydrochloride salt,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2,6-dimethoxy-4-pyrimidinamine,-   N˜4˜-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-N˜2˜,N˜2˜-dimethyl-2,4-pyrimidinediamine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-[(methylsulfanyl)methyl]-4-pyrimidinamine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-(methylsulfanyl)-6-(trifluoromethyl)-4-pyrimidinamine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-5-methoxy-2-(methylsulfanyl)-4-pyrimidinamine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-6-methyl-2-(methylsulfanyl)-4-pyrimidinamine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-5-methoxy-2-methyl-4-pyrimidinamine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-(ethylsulfanyl)-6-methyl-4-pyrimidinamine,-   N˜2˜-Cyclopropyl-N˜4˜-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]propyl}-2,4-pyrimidinediamine,-   2-{[4-({3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}amino)-2-pyrimidinyl]amino}-1-ethanol,-   2-[[4-({3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}amino)-2-pyrimidinyl](methyl)amino]-1-ethanol,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-(methylsulfanyl)-4-pyrimidinamine,-   N˜4˜-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-6-methyl-2,4-pyrimidinediamine,-   N˜4˜-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-N˜2˜,6-dimethyl-2,4-pyrimidinediamine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-phenyl-2-pyrimidinamine,-   N˜2˜-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-5-fluoro-2,4-pyrimidinediamine,-   N˜2˜-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-N˜4˜,N˜4˜,6-trimethyl-2,4-pyrimidinediamine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-(trifluoromethyl)-2-pyrimidinamine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-(propylsulfanyl)-2-pyrimidinamine,-   N˜2˜-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-N˜4˜-phenyl-2,4-pyrimidinediamine,-   N˜2˜-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-N˜4˜,6-dimethyl-2,4-pyrimidinediamine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}[1,8]naphthyridin-2-amine,-   2-{[2-({3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}amino)-4-pyrimidinyl]amino}-1-ethanol,-   2-[[2-({3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}amino)-4-pyrimidinyl](methyl)amino]-1-ethanol,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-(3-pyridinyl)-2-pyrimidinamine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-(3-thienyl)-2-pyrimidinamine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-pyrimidinamine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4,6-dimethoxy-2-pyrimidinamine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-(3-furyl)-2-pyrimidinamine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-(2-thienyl)-2-pyrimidinamine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-1H-purin-6-amine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-5-methylthieno[2,3-d]pyrimidin-4-amine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-7-methylthieno[3,2-d]pyrimidin-4-amine,-   N˜7˜-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-5-methyl[1,3]thiazolo[4,5-d]pyrimidine-2,7-diamine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-9-methyl-9H-purin-6-amine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-pyridinamine,-   5-Chloro-N-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]propyl}-2-pyridinamine,-   6-Chloro-N-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]propyl}-2-pyridinamine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-6-methyl-2-pyridinamine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-1,3-benzothiazol-2-amine,-   N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-1,3-benzoxazol-2-amine,-   6-Chloro-N-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]propyl}-2-pyrazinamine,-   6-Chloro-N-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]propyl}-3-pyridazinamine,-   6-({3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}amino)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2,6-dimethoxy-4-pyrimidinamine,-   N˜4˜-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-N˜2˜,N˜2˜-dimethyl-2,4-pyrimidinediamine,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-[(methylsulfanyl)methyl]-4-pyrimidinamine,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-5-methoxy-2-(methylsulfanyl)-4-pyrimidinamine,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-6-methyl-2-(methylsulfanyl)-4-pyrimidinamine,-   N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-5-methoxy-2-methyl-4-pyrimidinamine,    and-   N˜4˜-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-6-methyl-N˜2˜-phenyl-2,4-pyrimidinediamine.

The present invention further provides a process for the preparation ofa compound of formula (I) which comprises

(i) when T represents a group C(O)NH, reacting a compound of generalformulaR¹-(Q)_(m)-COL¹  (II)wherein L¹ represents a leaving group (e.g. a hydroxyl or halide, suchas chloride, group) and R¹, m and Q are as defined in formula (I), witha compound of general formula

or an acid addition salt thereof (e.g. trifluoroacetate) wherein n, R²,R³, V, W, X and R⁴ are as defined in formula (I); or(ii) when T represents a group C(O)NH and W represents a nitrogen atom,reacting a compound of general formula

wherein R¹, m, Q, T, n, R², R³ and V are as defined in formula (I), witha compound of general formulaL²-X—R⁴  (V)wherein L² represents a leaving group (e.g. a halogen atom) and X and R⁴are as defined in formula (I); or(iii) when T represents a group NH and m is 0, reacting a compound ofgeneral formulaR¹-L³  (VI)wherein L³ represents a leaving group (e.g. a halogen atom) and R¹ is asdefined in formula (I), with a compound of formula (III) as defined in(i) above; or(iv) when T represents a group NH, m is 1 and Q represents C₁-C₄alkylene, reacting a compound of general formulaR¹—(CH₂)_(p)—CHO  (VII)wherein p is 0, 1, 2 or 3 and R¹ is as defined in formula (I), with acompound of formula (III) as defined in (i) above; or(v) when T represents a bond and m is 0, reacting a compound of generalformulaR¹—(CR²R³)_(n)-L⁴  (VIII)wherein L⁴ represents a leaving group such as a halogen atom (e.g.chlorine) and n, R¹, R² and R³ are as defined in formula (I), with acompound of general formula

wherein W, X and R⁴ are as defined in formula (I);and optionally after (i), (ii), (iii), (iv) or (v) converting thecompound of formula (I) to a further compound of formula (I) and/orforming a pharmaceutically acceptable salt or solvate of the compound offormula (I).

The processes of the invention may conveniently be carried out in asolvent, e.g. an organic solvent such as dimethylformamide ordichloromethane at a temperature of, for example, 15° C. or above suchas a temperature in the range from 20 to 100° C.

Compounds of formula (III) in which W represents a nitrogen atom may beprepared by reacting a compound of general formula

in which n, R², R³ and V are as defined in formula (I) with a compoundof formula (V) as defined above.

Compounds of formula (X) can be prepared by reacting piperazine with acompound of general formulaH₂N—(CR²R³)_(n)-L⁵  (XI)wherein L⁵ represents a halogen atom such as a bromine atom and n, R²and R³ are as defined in formula (I).

Compounds of formula (III) in which W represents a group CH and Xrepresents an oxygen atom may be prepared by reacting a compound ofgeneral formula

in which R⁴ is as defined in formula (I), with a compound of formula(XI).

Compounds of formula (XII) may be prepared by reacting 4-piperidinolwith a compound of general formula (XIII), R⁴—OH, wherein R⁴ is asdefined in formula (I), in the presence of a coupling agent such asdiethyl azodicarboxylate and triphenylphosphine and in a solvent such asbenzene or tetrahydrofuran at a temperature typically in the range from20 to 30° C.

Compounds of formula (III) in which W represents a group CH and Xrepresents a group C(O) may be prepared by reacting a compound ofgeneral formula

wherein R⁴ is as defined in formula (I), with a compound of formula(XI).

Compounds of formula (III) in which W represents a group CH and Xrepresents a group CH(OH) may be prepared by reducing/hydrogenating acorresponding compound of formula (III) in which X represents C(O) usingtechniques known in the art.

Compounds of formula (III) in which W represents a group CH and Xrepresents a group NH may be prepared by reacting a compound of generalformula

in which R⁴ is as defined in formula (I), with a compound of formula(XI).

Compounds of formula (XV) may be prepared by reacting 4-piperidone witha compound of general formula (XVI), R⁴—NH₂, wherein R⁴ is as defined informula (I), in the presence of a reducing agent such as sodiumcyanoborohydride or sodium borohydride and in a solvent such as methanolor benzene at a temperature typically in the range from 20 to 90° C.

Compounds of formula (III) in which W represents a group CH and Xrepresents a group N(C₁-C₆ alkyl) may be prepared by alkylating acorresponding compound of formula (III) in which X represents a groupNH, using techniques conventional in the art.

Compounds of formula (IV) may be prepared by reacting a compound offormula (II) with a compound of formula (X).

Compounds of formulae II, V, VI, VII, VIII, IX, XI, XIII, XIV and XVIare either commercially available, are well known in the literature ormay be prepared easily using known techniques.

Compounds of formula (I) can be converted into further compounds offormula (I) using standard procedures. For example, compounds of formula(I) in which R¹ represents an alkoxy-substituted phenyl group can beconverted to compounds of formula (I) in which R¹ represents ahydroxy-substituted phenyl group by reaction with boron tribromide in asolvent such as dichloromethane. Further, compounds of formula (I) inwhich X represents C(O) can be converted to compounds of formula (I) inwhich X represents CH(OH) by reaction with triethylsilane andtrifluoroacetic acid in a solvent such as dichloromethane.

It will be appreciated by those skilled in the art that in the processesof the present invention certain functional groups such as hydroxyl oramino groups in the starting reagents or intermediate compounds may needto be protected by protecting groups. Thus, the preparation of thecompounds of formula (I) may involve, at an appropriate stage, theremoval of one or more protecting groups.

The protection and deprotection of functional groups is described in‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 2ndedition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).

The compounds of formula (I) above may be converted to apharmaceutically acceptable salt or solvate thereof, preferably an acidaddition salt such as a hydrochloride, hydrobromide, phosphate, acetate,fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate orp-toluenesulphonate.

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses the use of all geometric and optical isomers of thecompounds of formula (I) and mixtures thereof including racemates. Theuse of tautomers and mixtures thereof also form an aspect of the presentinvention.

The compounds of formula (I) have activity as pharmaceuticals, inparticular as modulators of chemokine receptor (especially CCR1 and/orCCR3) activity, and may be used in the treatment of autoimmune,inflammatory, proliferative and hyperproliferative diseases andimmunologically-mediated diseases including rejection of transplantedorgans or tissues and Acquired Immunodeficiency Syndrome (AIDS).

Examples of these conditions are:

-   -   (1) (the respiratory tract) obstructive airways diseases        including chronic obstructive pulmonary disease (COPD) such as        irreversible COPD; asthma, such as bronchial, allergic,        intrinsic, extrinsic and dust asthma, particularly chronic or        inveterate asthma (e.g. late asthma and airways        hyper-responsiveness); bronchitis; acute, allergic, atrophic        rhinitis and chronic rhinitis including rhinitis caseosa,        hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and        rhinitis medicamentosa; membranous rhinitis including croupous,        fibrinous and pseudomembranous rhinitis and scrofoulous        rhinitis; seasonal rhinitis including rhinitis nervosa (hay        fever) and vasomotor rhinitis; sarcoidosis, farmer's lung and        related diseases, fibroid lung and idiopathic interstitial        pneumonia;    -   (2) (bone and joints) rheumatoid arthritis, seronegative        spondyloarthropathies (including ankylosing spondylitis,        psoriatic arthritis and Reiter's disease), Behcet's disease,        Sjogren's syndrome and systemic sclerosis;    -   (3) (skin) psoriasis, atopical dermatitis, contact dermatitis        and other eczmatous dermitides, seborrhoetic dermatitis, Lichen        planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa,        urticaria, angiodermas, vasculitides, erythemas, cutaneous        eosinophilias, uveitis, Alopecia areata and vernal        conjunctivitis;    -   (4) (gastrointestinal tract) Coeliac disease, proctitis,        eosinopilic gastro-enteritis, mastocytosis, Crohn's disease,        ulcerative colitis, food-related allergies which have effects        remote from the gut, e.g., migraine, rhinitis and eczema;    -   (5) (other tissues and systemic disease) multiple sclerosis,        atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS),        lupus erythematosus, systemic lupus, erythematosus, Hashimoto's        thyroiditis, myasthenia gravis, type I diabetes, nephrotic        syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous        leprosy, sezary syndrome and idiopathic thrombocytopenia pupura;        and    -   (6) (allograft rejection) acute and chronic following, for        example, transplantation of kidney, heart, liver, lung, bone        marrow, skin and cornea; and chronic graft versus host disease.

Thus, the present invention provides a compound of formula (I), or apharmaceutically-acceptable salt or solvate thereof, as hereinbeforedefined for use in therapy.

In a further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined in the manufacture of amedicament for use in therapy.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

The invention also provides a method of treating an inflammatory diseasein a patient suffering from, or at risk of, said disease, whichcomprises administering to the patient a therapeutically effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as hereinbefore defined.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated.

The compounds of formula (I) and pharmaceutically acceptable salts andsolvates thereof may be used on their own but will generally beadministered in the form of a pharmaceutical composition in which theformula (I) compound/salt/solvate (active ingredient) is in associationwith a pharmaceutically acceptable adjuvant, diluent or carrier.Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% w (per cent by weight), morepreferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w,and even more preferably from 0.10 to 50% w, of active ingredient, allpercentages by weight being based on total composition.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as hereinbefore defined, in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined, with a pharmaceuticallyacceptable adjuvant, diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. tothe lung and/or airways or to the skin) in the form of solutions,suspensions, heptafluoroalkane aerosols and dry powder formulations; orsystemically, e.g. by oral administration in the form of tablets,capsules, syrups, powders or granules, or by parenteral administrationin the form of solutions or suspensions, or by subcutaneousadministration or by rectal administration in the form of suppositoriesor transdermally.

The invention will now be further explained by reference to thefollowing illustrative examples.

EXAMPLE 14-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-2-[2-(dimethylamino)-2-oxoethoxy]benzamide

(i) tert-Butyl 4-(3,4-dichlorophenoxy)-1-piperidinecarboxylate

Diethyl azodicarboxylate (12.6 ml) was added to a solution oftriphenylphosphine (20.8 g) in tetrahydrofuran (300 ml) at 0° C. After15 minutes 3,4-dichlorophenol (12.9 g) was added, after a further 10minutes tert-butyl 4-hydroxy-1-piperidinecarboxylate (14.5 g) intetrahydrofuran (100 ml) was added dropwise over 0.5 hour. The solutionwas stirred at room temperature for 5 hours and concentrated to a smallvolume. The residue was partitioned between ether and brine. The organicphase was separated, dried and evaporated to a gum. Purification bychromatography (ethyl acetate:isohexane 95:5) gave the sub-titledproduct as an oil (20 g).

MS: APCI(+ve): 246 (M-BOC+2H)

(ii) 4-(3,4-Dichlorophenoxy)piperidine

The product from step (i) was dissolved in dichloromethane (200 ml) andtrifluoroacetic acid (100 ml) was added. After 18 hours at roomtemperature the solution was evaporated and the resultant gum trituratedunder ether to give the sub-titled product as a solid (16.2 g).

(iii) tert-Butyl 2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethylcarbamate

The product from step (ii) (6.55 g) was dissolved in DMF (50 ml) andtriethylamine (7.9 ml) was added. tert-Butyl 2-bromoethylcarbamate (4.3g) in DMF (5 ml) was added and the solution stirred at room temperaturefor 3 days. Ethyl acetate and water were added, the organic phaseseparated, dried and evaporated to a gum. Purification by chromatography(dichloromethane:methanol 95:5) gave the sub-titled product as a gum(5.7 g).

MS: APCI(+ve): 389 (M+H).

(iv) 2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethylaminetrifluoroacetate

The product from step (iii) was dissolved in dichloromethane (200 ml)and trifluoroacetic acid (100 ml) added. After 18 hrs at roomtemperature the solvent was evaporated and the resultant gum trituratedunder ether to give the sub-titled product as a solid (5.7 g).

MS: APCI(+ve): 290 (M+H).

(v) 2-(Dimethylamino)-2-oxoethyl4-chloro-2-[2-(dimethylamino)-2-oxoethoxy]benzoate

A mixture of 4-chloro-2-hydroxybenzoic acid (5 g), Cs₂CO₃ (17.5 g) and2-chloro-N,N-dimethylacetamide (6.6 g) was stirred and heated at 70° C.for 3 hours. Water and ethyl acetate were added, the organic phaseseparated, dried and concentrated to a gum which was purified bychromatography (ethyl acetate:methanol, 9:1) to give the sub-titledproduct as a solid (8.0 g).

MS: APCI(+ve) 343 (M+H).

Melting point: 140-141° C.

(vi) 4-Chloro-2-[2-(dimethylamino)-2-oxoethoxy]benzoic acid

The product from step (v) (1.0 g) was dissolved in a 2:1 water:methanolmixture (15 ml) and LiOH.H₂O added. After 2 hours 2M aqueous HClsolution and ethyl acetate were added, the organic phase separated,dried and concentrated to give the sub-titled product as a solid (1.2g).

MS: APCI(+ve) 258 (M+H).

Melting point: 141-142° C.

(vii)4-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-2-[2-(dimethylamino)-2-oxoethoxy]benzamide

The product from step (vi) (0.3 g) and N,N-carbonyldiimidazole (0.19 g)were dissolved in DMF (20 ml) and the solution stirred at roomtemperature for 1 hour. The product from step (iv) (0.42 g) andtriethylamine (0.32 ml) were added. After 20 hours water and ether wereadded, the organic phase separated, dried and concentrated to a gumwhich was purified by chromatography (dichloromethane:methanol, 93:7) togive the titled product as a solid (0.38 g).

MS: ESI 528.12 (M+H).

¹H NMR: δ(DMSO) 9.17 (t, 1H), 7.88 (d, 1H), 7.48 (d, 1H), 7.38 (d, 1H),7.24 (d, 1H), 7.13 (dd, 1H), 6.99 (dd, 1H), 5.11 (s, 2H), 4.32 (m, 1H),3.42 (m, 2H), 2.99 (s, 3H), 2.88 (s, 3H), 2.73 (m, 2H), 2.50 (m, 2H),2.30 (m, 2H), 1.90 (m, 2H), 1.59 (m, 2H).

Melting point: 139-40° C.

EXAMPLE 2N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-ethoxybenzamidehydrochloride

The product of Example 1 step (iv) (0.4 g) was dissolved in DMF (10 ml),PyBrop (0.541 g), 3-ethoxybenzoic acid (0.167 g ) andN,N-di-isopropylethylamine (0.5 g) were added. After 18 hours at roomtemperature chloroform and aqueous NaHCO₃ solution were added. Theorganic phase was separated, dried and concentrated to leave a gum whichwas purified by chromatography (ethyl acetate:methanol 97:3) to give anoil. Addition of 1.0M ethereal hydrogen chloride solution gave thetitled product as a solid (0.14 g).

MS: ESI 437.14 (M+H).

¹H NMR: δ(DMSO) 8.87 (bs, 1H), 7.50 (m, 3H), 7.40 (m, 2H), 7.06 (m, 2H),4.83/4.62 (m, 1H), 4.08 (q, 2H), 3.67 (m, 3H), 3.47 (m, 1H), 3.17 (m,3H), 2.20 (m, 2H), 2.03 (m, 2H), 1.34 (t, 3H).

Melting point: 191-193° C.

EXAMPLE 3N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-isopropoxybenzamide

Prepared by the same method as Example 2 using 4-isopropoxybenzoic acidwithout the addition of 1.0 M ethereal hydrogen chloride solution togive the titled product as a solid (0.12 g).

MS: ESI 451.14 (M+H).

¹H NMR: δ(DMSO) 8.22 (t, 1H), 7.8 (m, 2H), 7.49 (d, 1H), 7.25 (d, 1H),7.00 (m, 3H), 4.7 (m, 1H), 4.45 (m, 1H), 3.36 (m, 2H), 2.73 (m, 2H),2.48 (m, 2H), 2.29 (m, 2H), 1.91 (m, 2H), 1.60 (m, 2H), 1.28 (s, 3H),1.27 (s, 3H).

Melting point: 113-15° C.

EXAMPLE 4N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-ethoxybenzamide

Prepared by the same method as Example 2 using 4-etboxybenzoic acidwithout the addition of 1.0 M ethereal hydrogen chloride solution togive the titled product as a solid (0.1 g).

MS: ESI 437.14 (M+H).

¹H NMR: δ(DMSO) 8.22 (t, 1H), 7.79 (d, 2H), 7.49 (d, 1H), 7.25 (d, 1H),7.00 (m, 3H), 4.5 (m, 1H), 4.07 (q, 2H), 3.37 (q, 2H), 2.73 (m, 2H),2.47 (m, 2H), 2.30 (m, 2H), 1.91 (m, 2H), 1.60 (m, 2H), 1.34 (t, 3H).

Melting point: 118-20° C.

EXAMPLE 5N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-(trifluoromethoxy)benzamidehydrochloride

Prepared by the same method as Example 2 using 3-trifluoromethoxybenzoicacid to give the titled product as a solid (0.12 g).

MS: ESI 477.09 (M+H).

¹H NMR: δ(DMSO) 10.42 (bs, 1H), 9.11 (bm, 1H), 8.0 (d, 1H), 7.88 (s,1H), 7.6 (m, 3H), 7.37 (m, 1H), 7.06 (m, 1H), 4.70 (m, 1H), 3.71 (m,3H), 3.48 (d, 1H), 3.20 (m, 4H), 2.2 (m, 4H).

Melting point: 180-82° C.

EXAMPLE 6N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-methoxybenzamide

Prepared by the same method as Example 2 using 4-methoxybenzoic withoutthe addition of 1.0 M ethereal hydrogen chloride solution to give thetitled product as a solid (0.11 g).

MS: ESI 423.12 (M+H).

¹H NMR: δ(DMSO) 8.42 (t, 1H), 7.81 (m, 2H), 7.49 (d, 1H), 7.25 (d, 1H),6.98 (s, 3H), 4.4 (m, 1H), 3.8 (s, 3H), 3.35 (q, 2H), 2.73 (m, 2H), 2.47(m, 2H), 2.30 (m, 2H), 1.91 (m, 2H), 1.60 (m, 2H).

Melting point: 110-12° C.

EXAMPLE 7N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-(trifluoromethoxy)benzamidehydrochloride

Prepared by the same method as Example 2 using 4-trifluoromethoxybenzoicacid to give the titled product as a solid (0.19 g).

MS: ESI 477 (M+H).

¹H NMR: δ(DMSO) 10.5 (bs, 1H), 9.06 (m, 1H), 8.07 (dd, 2H), 7.55 (t,1H), 7.49 (d, 2H), 7.36 (dd, 1H), 7.10-7.02 (m, 1H), 4.72 (m, 1H), 3.70(m, 3H), 3.47 (d, 1H), 3.14 (m, 2H), 2.25 (m, 2H), 2.02 (m, 2H).

Melting point: 184-187° C.

EXAMPLE 8 N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-furamidehydrochloride

Prepared by the same method as Example 2 using furan-2-carboxylic acidto give the titled product as a solid (0.14 g).

MS: ESI 383.09 (M+H).

¹H NMR: δ(DMSO) 10.43 (bm, 1H), 8.76 (t, 1H), 7.87 (s, 1H), 7.55 (t,1H), 7.36 (dd, 1H), 7.21 (d, 1H), 7.06 (m, 1H), 6.64 (dd, 1H), 4.83-4.61(m, 1H), 3.65 (m, 3H), 3.45 (d, 1H), 3.08 (m, 4H), 2.1 (m, 4H).

Melting point: 225-28° C.

EXAMPLE 9N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-phenylacetamidehydrochloride

Prepared by the same method as Example 2 using phenylacetic acid to givethe titled product as a solid (0.12 g).

MS: ESI 407 (M+H).

¹H NMR: δ(DMSO) 10.28 (bm, 1H), 8.46 (bm, 1H), 7.56 (t, 1H), 7.3 (m,6H), 7.10 (m, 1H), 4.81/4.58 (m, 1H), 3.58 (d, 1H), 3.46 (m, 4H), 3.10(m, 4H), 2.15 (m, 5H).

Melting point: 135-38° C.

EXAMPLE 10N-{2-[4(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-methoxybenzamidehydrochloride

The product of Example 1 step (iv) (2.0 g) was dissolved indichloromethane (490 ml), triethylamine (1.85 ml) and 3-methoxybenzoylchloride (0.66 g) were added. After 72 hours at room temperature, waterwas added, the organic phase separated, dried and concentrated to a gum.The product was dissolved in dichloromethane and treated with 1.0Methereal hydrogen chloride solution to give the titled product as asolid (0.88 g).

MS: ESI 423.12 (M+H).

¹H NMR: δ(DMSO) 10.6-10.5 (m, 1H), 9.92 (s, 1H), 7.54 (m, 3H), 7.38 (m,2H), 7.08 (m, 2H), 4.84/4.62 (m 1H), 3.82 (s, 3H), 3.45 (m, 8H), 2.27(m, 4H).

Melting point: 72-73° C.

EXAMPLE 113-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamidehydrochloride

The product of Example 1 step (iv) (0.15 g) was dissolved in DMF (3 ml),N,N-di-isopropylethylamine (0.3 ml) and 3-chlorobenzoyl chloride (0.054ml) were added. After 2 hours at room temperature, water and ethylacetate were added, the organic phase separated dried and concentrated.The residue was purified by chromatography (dichloromethane:methanol,95:5) to give an oil which was dissolved in ether and 1.0M etherealhydrogen chloride solution added to give the titled product as a solid(0.12 g).

MS: ESI 427.07 (M+H).

¹H NMR: δ(DMSO) 8.42 (t, 1H), 7.94-7.84 (m, 2H), 7.49 (d, 1H), 7.29 (m,3H), 6.98 (dd, 1H), 4.44 (m, 1H), 3.36 (m, 2H), 2.74 (m, 2H), 2.48 (m,2H), 2.29 (bt, 2H), 1.92 (m, 2H), 1.60 (m, 2H).

Melting point: 118° C.

EXAMPLE 12N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-fluorobenzamide

Prepared by the same method as Example 11 using 4-fluorobenzoyl chloridewithout the addition of 1.0 M ethereal hydrogen chloride solution togive the titled product as a solid (0.1 g).

MS: ESI 411.10 (M+H).

¹H NMR: δ(DMSO) 10.46 (bs, 1H), 9.04 (s, 1H), 7.98 (s, 1H), 7.90 (d,1H), 7.58 (m, 3H), 7.36 (dd, 1H), 7.05 (m, 1H), 4.84/4.60 (m, 1H), 3.69(m, 3H), 3.48 (bd, 1H), 3.20 (m, 4H), 2.15 (m, 4H).

Melting point: 192° C.

EXAMPLE 13N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-fluorobenzamidehydrochloride

Prepared by the same method as Example 11 using 3-fluorobenzoyl chlorideto give the titled product as a solid (0.09 g).

MS: ESI 411.10 (M+H).

¹H NMR: δ(DMSO) 10.67 (bs, 1H), 9.06 (s, 1H), 7.80 (m, 2H), 7.55 (m,2H), 7.40 (m, 2H), 7.05 (m, 1H), 4.84/4.63 (m, 1H), 3.70 (m, 3H), 3.28(m, 3H), 2.20 (m, 4H).

Melting point: 225° C.

EXAMPLE 14N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-hydroxybenzamidehydrochloride

The product of Example 10 (0.15 g) was dissolved in dichloromethane (10ml) and a solution of 1.0M BBr₃ in dichloromethane (4 ml) added. After16 hours at room temperature the solvent was removed by evaporation,methanol was added and the solution concentrated. The residue wasdissolved in 2M aqueous HCl solution, concentrated to dryness and theresidue triturated under ether to give the titled product as a solid(0.1 g).

MS: ESI 409.10 (M+H).

¹H NMR: δ(DMSO) 9.98-9.4 (bs, 2H), 8.71 (t, 1H), 7.6 (dd, 1H), 7.4-7.2(m, 4H), 7.05 (m, 1H), 6.95 (dd, 1H), 4.65 (m, 1H), 3.40 (m, 8H), 2.0(m, 4H).

Melting point: 83-4° C.

EXAMPLE 15N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-[2-(methylamino)-2-oxoethoxy]benzamidehydrochloride

(i) [1-(2-Aminoethyl)-4-piperidinyl](4-chlorophenyl)methanonetrifluoroacetate

To a solution of (4-chlorophenyl)(4-piperidinyl)methanone hydrochloride(2.5 g) and tert-butyl 2-bromoethylcarbamate (2.1 g) in DMF was addedtriethylamine (2.9 g), after 72 hours at room temperature water andether were added. The organic phase was separated, dried andconcentrated. The residue was dissolved in dichloromethane (40 ml),trifluoroacetic acid (10 ml) added and the solution left for 20 hours.Evaporation of the solvent gave a sticky solid which was trituratedunder ether to give the sub-titled product as a solid (2.5 g).

(ii) N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-methoxybenzamidehydrochloride

The product of step (i) (2.5 g) was dissolved in dichloromethane (20ml), triethylamine (0.75 ml) and 3-methoxybenzoyl chloride (0.276 g)were added. After 16 hours, water was added, the organic phaseseparated, dried and concentrated to a gum. Purification bychromatography (ethyl acetate) gave a gum, which was treated with 1.0Methereal hydrogen chloride solution to give the sub-titled product as asolid (0.3 g).

MS: ESI 401.16 (M+H).

¹H NMR: δ(DMSO) 10.3 (bm, 1H), 8.95 (t, 1H), 8.0 (m, 2H), 7.6 (m, 2H),7.5 (m, 2H), 7.4 (t, 1H), 7.05 (m, 1H), 3.8 (s, 3H), 3.68 (m, 4H), 3.28(m, 5H), 2.0 (m, 4H).

Melting point: 196-7° C.

(iii) N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-hydroxybenzamidehydrochloride

Prepared by the method of Example 14 using the product of step (ii)above (0.24 g) to give the sub-titled product as a solid (0.20 g).

MS: ESI 387.14 (M+H).

¹H NMR: δ(DMSO) 8.62 (t, 1H), 8.05 (dd, 2H), 7.6 (dd, 2H), 7.25 (m, 3H),6.95 (m, 1H), 4.26 (m, 9H), 2.0 (m, 4H).

Melting point: 90-91° C.

(iv)N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-[2-(methylamino)-2-oxoethoxy]benzamidehydrochloride

The product of step (iii) above (0.10 g) was dissolved in DMF (3 ml),Cs₂CO₂ (0.23 g) and 2-chloro-N-methylacetamide (0.26 g) were added andthe mixture heated at 80° C. for 16 hours. The mixture was cooled toroom temperature, water and ethyl acetate were added and the organicphase separated. Evaporation of the solvent gave a gum which was treatedwith 1.0M ethereal hydrogen chloride solution to give the titled productas a solid (0.05 g).

MS: ESI 458.18 (M+H).

¹H NMR: δ(DMSO) 10.6-10.2 (bm, 1H), 8.95 (bm, 1H), 8.1 (m, 2H), 7.55 (m,8H), 7.14 (bd, 1H), 4.54 (s, 2H), 4.0 (m, 1H), 3.4 (m, 8H), 2.65 (d,3H), 2.0 (m, 4H).

Melting point: 69-70° C.

EXAMPLE 162-[3-{2-[4-(4-Fluorobenzoyl)-1-piperidinyl]ethyl}-2,4-dioxo-3,4-dihydro-1(2H)-quinazolinyl]-N,N-dimethylacetamidehydrochloride

3-{2-[4-(4-Fluorobenzoyl)-1-piperidinyl]ethyl}-2,4(1H,3H)-quinazolinediodissolved in DMF (5 ml) and NaH (60% dispersion in mineral oil) added.After 0.5 hours, 2-chloro-N,N-dimethylacetamide was added and thesolution stirred at room temperature for 16 hours. Water and ethylactetate were added, the organic phase separated, dried and concentratedto an oil. Purification by chromatography (dichloromethane:methanol95:5) gave an oil which was treated with 1.0 M ethereal hydrogenchloride-solution to-give the titled product as a solid (0.15 g).

MS: ESI 481.22 (M+H).

¹H NMR: δ(DMSO) 8.08 (m, 3H), 7.76 (t, 1H), 7.40 (t, 2H), 7.32 (m, 2H),5.05 (s, 2H), 4.36 (m, 1H), 3.76 (m, 3H), 3.39 (m, 2H), 3.15 (s, 3H),2.87 (s, 3H), 2.02 (m, 2H), 1.81 (m, 2H), 1.28 (m, 2H).

Melting point: 245-246° C.

EXAMPLE 17N-{2-[4-(3,4-Dichlorobenzoyl)-1-piperazinyl]ethyl}-3-methoxybenzamidehydrochloride

(i) tert-Butyl 2-(1-piperazinyl)ethylcarbamate

A mixture of benzaldehyde (21 g) and 1-(2-aminoethyl)piperazine (25.8 g)was stirred and heated under a Dean and Stark water separator for 20hours. The cooled solution was treated portionwise withdi-tert-butyldicarbonate (48 g), stirred for 72 hours and concentrated.The residue was treated with 1M aqueous KHSO₄ solution (220 ml), stirredfor 24 hours, ether was added and the organic phase separated. Theaqueous phase was treated with 2M NaOH solution, dichloromethane wasadded and the organic phase separated. The combined organic phase waswashed with brine, dried and concentrated to give the sub-titled productas an oil (30 g).

MS: APCI(+ve) 230 (M+H).

¹H NMR δ(CDCl₃) 3.43 (t, 4H), 2.8 (t, 2H), 2.45 (m, 6H), 1.5 (s, 9H).

(ii) tert-Butyl 2-[4-(3,4-dichlorobenzoyl)-1-piperazinyl]ethylcarbamate

The product from step (i) above (3 g) was dissolved in pyridine (12 ml),3,4-dichlorobenzoyl chloride (2.05 g) was added and the mixture stirredat room temperature for 18 hours. A solid was collected by filtrationand purified by chromatography (dichloromethane:methanol: 0.880 NH₄OH,90:9:1) to give the sub-titled product as an oil (3.59 g).

MS: APCI(+ve) 364 (M+H).

¹H NMR δ(CDCl₃) 7.33 (m, 3H), 7.04 (m, 1H), 6.76 (bs, 1H), 3.86 (s, 3H),3.55 (q, 2H), 3.45 (t, 4H), 2.61 (t, 3H), 2.46 (t, 4H), 1.46 (s, 9H).

(iii) [4-(2-Aminoethyl)-1-piperazinyl](3,4-dichlorophenyl)methanonetrifluoroacetate

The product from step (ii) above (3.3 g) was dissolved indichloromethane (50 ml) and trifluoroacetic acid (10 ml) added. After 16hours at room temperature the solvent was removed to give the sub-titledproduct as an oil (5.9 g).

MS: APCI(+ve) 264 (M+H).

(iv)N-{2-[4-(3,4-Dichlorobenzoyl)-1-piperazinyl]ethyl}-3-methoxybenzamidehydrochloride

The product from step (iii) above (0.15 g) was dissolved in pyridine (2ml) and 3-methoxybenzoyl chloride (0.064 g) added. After 16 hours atroom temperature, water and ethyl acetate were added, the organic phaseseparated, dried and concentrated to an oil. Purification bychromatography (dichloromethane:methanol, 95:5) gave an oil which wastreated with 1.0M ethereal hydrogen chloride solution to give the titledproduct as a solid (0.043 g).

MS: ESI 436.12 (M+H).

¹H NMR: δ(DMSO) 8.8 (bt, 1H), 7.34 (m, 2H), 7.43 (m, 4H), 7.14 (m, 1H),3.82 (s, 3H), 3.48 (m, 12H).

Melting point: 230° C.

EXAMPLE 183,4-Dichloro-N-{2-[4-(3,4-dichlorobenzoyl)-1-piperazinyl]ethyl}benzamide

A solution of benzaldehyde (5.3 g) and 1-(2-aminopiperazine) (6.45 g) intoluene (100 ml) was heated under a Dean and Stark water separator for 4hours. The solution was cooled to room temperature and triethylamine(5.05 g) added. A solution of 3,4-dichlorobenzoyl chloride (10.48 g) intoluene (50 ml) was added dropwise, the solution stirred at roomtemperature for 18 hours and water added. The organic phase wasseparated, dried and concentrated to a residue which was treated with 1Naqueous KHSO₄ solution (65 ml). The mixture was stirred vigorously for 4hours, ether was added, the aqueous phase separated and NaOH added.CHCl₃ was added, the organic phase separated, dried and concentrated toa gum. Purification by chromatography (dichloromethane:triethylamine,95:5) gave the titled product as a foam (0.25 g).

MS: ESI 474.03 (M+H).

¹H NMR: δ(DMSO) 8.8 (bt, 1H), 7.34 (m, 2H), 7.43 (m, 4H), 7.14 (m, 1H),3.82 (s, 3H), 3.48 (m, 12H).

EXAMPLE 19

4-Chloro-N-{2-[4-(3,4-dichlorobenzoyl)-1-piperazinyl]ethyl}-2-[2-(dimethylamino)-2-oxoethoxy]benzamidehydrochloride

The product of Example 26 step (ii) (0.3 g), 3,4-dichlorobenzoylchloride (0.1 g) and triethylamine (0.15 g) were dissolved indichloromethane (15 ml). After 20 hours at room temperature water wasadded, the organic phase separated, dried and evaporated to give a gum.Purification by chromatography (dichloromethane:methanol, 20:1) gave asolid which was treated with 1.0M ethereal hydrogen chloride solution togive the titled product as a solid (0.1 g).

MS: ESI 541.11 (M+H).

¹H NMR δ(DMSO-D6) 9.54 (t, 1H), 7.91 (d, 1H), 7.74 (m, 2H), 7.43 (m,2H), 7.18 (d, 1H), 5.12 (s, 2H), 3.2-3.8 (m, 12H), 2.99 (s, 3H), 2.88(s, 3H).

Melting point: 226-7° C.

EXAMPLE 20N˜7˜-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-5-methyl[1,3]thiazolo[4,5-d]pyrimidine-2,7-diamine

MS: APCI(+ve) 453 (M+1).

EXAMPLE 21N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-9-methyl-9H-purin-6-amine

MS: APCI(+ve) 421 (M+1).

EXAMPLE 22N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-1,3-benzothiazol-2-amine

MS: APCI(+ve) 422 (M+1).

EXAMPLE 23N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-1,3-benzoxazol-2-amine

MS: APCI(+ve) 406 (M+1).

EXAMPLE 246-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-2-pyrazinamine

MS: APCI(+ve) 403 (M+1).

EXAMPLE 256-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-3-pyridazinamine

MS: APCI(+ve) 403 (M+1).

EXAMPLE 266-({2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}amino)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione

MS: APCI(+ve) 427 (M+1).

EXAMPLE 27N-{1-[4-(3,4-Dichlorophenoxy)-piperidin-1-ylmethyl]-2-methyl-propyl}-4-methyl-benzamide,hydrochloride

(i)N-{1-{4-(3,4-Dichlorophenoxy)-piperidine-1-carbonyl]-2-methyl-propyl}-acetamide

N-Boc Valine (1.13 g) was dissolved in dichloromethane (5 ml) and EDC(0.99 g) added, after 5 min the product according to Example 1 step (ii)(1.44 g) in dichloromethane (5 ml) was added in one portion. After 3hours at room temperature, aqueous sodium bicarbonate solution and ethylacetate were added. The organic phase was separated and the solventremoved to give the sub-titled compound as an oil (1.57 g) which wasused in the next step without further purification.

(ii)2-amino-1-[4-(3,4-dichlorophenoxy)-piperidine-1-yl]-3-methyl-butan-1-one

The product of step (i) (1.57 g) was dissolved in dichloromethane (14ml) and trifluoroacetic acid (4 ml) added. After 2 hours at roomtemperature the solvent was removed, ethyl acetate and 2N aqueous NaOHsolution were added to give pH 8.0. The organic phase was separated andconcentrated to give the sub-titled product as an oil (1.24 g) which wasused in the next step without further purification.

(iii)1-[4-(3,4-Dichlorophenoxy)-piperidin-1-ylmethyl]-2-methyl-propylamine

The product of step (ii) (1.12 g) was dissolved in THF (10 ml) andBorane/THF complex (22.7 ml) added. The mixture was heated under refluxfor 2 hours and cooled. The solvent was evaporated, the productdissolved in methanol (5 ml) and 50% aqueous HCl solution added. Themixture was heated to 70° C. for 1 hour and cooled to room temperature.The solvent was removed, ethyl acetate and 2N aqueous NaOH solution wereadded to give pH 9.0. The organic phase was separated and the solventevaporated to give the sub-titled compound as an oil (0.98 g) which usedwithout further purification.

(iv)N-{1-[4-(3,4-Dichlorophenoxy)-piperidin-1-ylmethyl]-2-methyl-propyl}-4-methyl-benzamide,hydrochloride

The product of step (iii) (0.2 g) was dissolved in dichloromethane (5ml), triethylamine (0.126 ml) and 4-methylbenzoyl chloride (0.097 ml)were added. After 2 hours at room temperature, ethyl acetate and aqueousNaHCO₃ solution were added, the organic phase separated and the solventremoved to leave an oil. Purification by reverse phase HPLC (with agradient eluent system (25% MeCN/NH₄OAc_(aq) (0.1%) to 95%MeCN//NH₄OAc_(aq) (0.1%)) gave a gum. Addition of 1.0M ethereal hydrogenchloride solution gave the titled product as a solid (0.104 g).

Melting point: 131-132° C.

MS: ESI 450 (M+H).

¹H NMR: δ(DMSO) 8.45 (t, 1H), 7.00-7.90 (m, 7H), 4.79 (br s, 1H),4.24-4.30 (m, 1H), 3.10-3.42 (m, 5H), 2.36 (s, 3H), 1.88-2.40 (m, 5H),0.92 (t, 6H).

EXAMPLE 28N-{1-[4-(3,4-Dichloro-phenoxy)-piperidin-1-ylmethyl]-2-methyl-propyl}-3-methoxy-benzamide,hydrochloride

The product according to Example 27 step (iii) dissolved indichloromethane (4 ml), triethylamine (0.090 ml) and 3-methoxybenzoylchloride (0.077 ml) were added. After 2 hours at room temperature,NaHCO₃ was added, the product extracted with ethyl acetate, the combinedorganic extracts dried with Na₂SO₄ and concentrated. Purification withreverse phase HPLC (with a gradient eluent system (25% MeCN/NH₄OAc_(aq)(0.1%) to 95% MeCN//NH₄OAc_(aq) (0.1%)) gave a gum. The product wasdissolved in methanol and treated with 1.0M ethereal Hydrogen chloridesolution to give the product as a solid (0.045 g).

MS: ESI 465 (M+H).

¹H NMR: δ(DMSO) 8.58-8.63 (m, 1H), 7.01-7.58 (m, 6H), 4.80 (br s, 1H),4.23-4.59 (m, 1H), 3.83 (s, 3H), 3.04-3.60 (m, 4H), 1.89-2.14 (m, 5H),0.85 (m, 6H).

EXAMPLE 29N-{2-[4-(3,4-Dichloroanilino)-1-piperidinyl]ethyl}-3-methoxybenzamidedihydrochloride

(i) tert-Butyl 4-(3,4-dichloroanilino)-1-piperidinecarboxylate

A solution of 3,4-dichloroaniline (5 g),N-tert-butoxycarbonyl-4-piperidone (11.7 g), sodiumtriacetoxyborohydride (19.7 g) and acetic acid (7 ml) in dichloroethane(150 ml) was stirred for 16 hours. 2M NaOH solution and ether wereadded, the organic phase separated, dried and concentrated. The residuewas triturated under an isohexane:ethyl acetate, 4:1 mixture and thesub-titled product collected as a solid (7.25 g).

MS: APCI(+ve) 345 (M+H).

¹H NMR: δ(DMSO) 7.23 (d, 1H), 6.77 (d, 1H), 6.57 (dd, 1H), 5.99 (d, 1H),3.85 (bd, 2H), 3.40 (m, 1H), 2.90 (bm, 2H), 1.85 (m, 2H), 1.39 (s, 9H),1.19 (m, 2H).

(ii) N-(3,4-Dichlorophenyl)-4-piperidinamine trifluoroacetate

The product of step (i) above (6.5 g) was dissolved in dichloromethane(75 ml) and trifluoroacetic acid (25 ml) added. After 72 hours at roomtemperature the solution was evaporated and the residue triturated underether to give the sub-titled product as a solid (6.3 g).

MS: APCI(+ve) 245/7 (M+H).

¹H NMR: δ(DMSO) 8.65 (bs, 1H), 8.50 (bs, 1H), 7.26 (d, 1H), 6.81 (d,1H), 6.60 (dd, 1H), 6.19 (bs, 1H), 3.53 (bs, 1H), 3.30 (m, 2H), 3.0 (m,2H), 202 (m, 2H), 1.50 (m, 2H).

(iii) tert-Butyl 2-[4-(3,4-dichloroanilino)-1-piperidinyl]ethylcarbamate

The product from step (ii) above (2.0 g),N-tert-butoxycarbonyl-2-bromoethanamine (1.0 g) andN,N-di-isopropylethylamine (3.7 ml) were dissolved in DMF (25 ml) andstirred for 16 hours. Water and ethyl acetate were added, the organicphase separated, dried and evaporated to give a gum. Purification bychromatography (dichloromethane:methanol, 95:5) gave the sub-titledproduct as a solid (1.25 g).

MS: APCI(+ve) 388/90 (M+H).

¹H NMR: δ(DMSO) 7.22 (d, 1H), 6.73 (d, 1H), 6.62 (t, 1H), 6.54 (dd, 1H)5.94 (d, 1H), 3.17 (m, 1H), 3.02 (m, 2H), 2.77 (bd, 2H), 2.31 (t, 3H),2.06 (t, 2H), 1.84 (bd, 2H), 1.35 (m, 11H).

(iv) 1-(2-Aminoethyl)-N-(3,4-dichlorophenyl)-4-piperidinaminetriluoroacetate

The product from step (iii) above (1.2 g) was dissolved indichloromethane (30 ml) and trifluoroacetic acid (10 ml) added. After 72hours at room temperature the reaction mixture was evaporated andresidue triturated under ether to give the sub-titled product as a solid(1.6 g).

MS: APCI(+ve) 288/90 (M+H).

(v)N-{2-[4-(3,4-Dichloroanilino)-1-piperidinyl]ethyl}-3-methoxybenzamidedihydrochloride

The product of step (iv) above (0.5 g) and triethylamine (1.1 ml) weredissolved in DMF (10 ml), 3-methoxybenzoylchloride (0.11 ml) was addeddropwise. After 2 hours, water and ethyl acetate were added, the organicphase separated, dried and evaporated. Purification of the residue bychromatography (dichloromethane:methanol, 95:5) gave an oil which wastreated with 1.0M ethereal hydrogen chloride solution to give the titledproduct as a solid (0.15 g).

MS: ESI 422.14 (M+H).

¹H NMR: δ(DMSO) 10.44 (bs, 1H), 8.93 (t, 1H) 7.51 (m, 2H), 7.40 (t, 1H),7.26 (d, 1H), 7.11 (dd, 1H), 6.81 (d, 1H), 6.60 (dd, 1H), 3.82 (s, 3H),2.68 (m, 4H), 3.25 (m, 5H), 2.09 (bd, 2H), 1.76 (m, 2H).

Melting point: 170° C.

EXAMPLE 30N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-N-(3-methoxybenzyl)aminedihydrochloride

A suspension of the product of Example 1 step (iv) (0.11 g) in a mixtureof DMF (1.5 ml) and 1,2-dichloroethane (3 ml) was stirred under anatmosphere of nitrogen. Sodium triacetoxyborohydride (0.097 g),3-methoxybenzaldehyde (0.041 g) and triethylamine (0.046 g) were addedand the mixture stirred for 18 hours at room temperature. Chloroform andaqueous NaHCO₃ solution were added, the organic phase separated, driedand concentrated to a gum. Purification by chromatography(chloroform:triethylamine:methanol, 89:10:1) gave an oil which wastreated with 1.0M ethereal hydrogen chloride solution to give the titledproduct as a solid (0.067 g).

MS: ESI 409.14 (M+H).

¹H NMR: δ(DMSO) 7.50 (d, 1H), 7.30 (m, 3H), 7.12 (d, 1H), 7.03 (dd, 1H),6.97 (dd, 1H), 4.71 (bm, 1H), 4.18 (s, 2H), 3.80 (s, 3H), 3.45 (bm, 4H),2.23 (m, 6H), 2.04 (m, 2H),

Melting point: 247-51° C.

EXAMPLE 313-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-6-methoxy-2,4(1H,3H)-quinazolinedione

(i)2-Amino-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-5-methoxybenzamide

Prepared by the method of Example 2 using the product from Example 1step (iv) (1.0 g) and 2-amino-5-methoxybenzoic acid (0.418 g) withoutthe addition of 1.0M ethereal hydrogen chloride solution to give an oilwhich was purified by chromatography (dichloromethane:methanol, 95:5) togive the sub-titled product as an oil (0.82 g).

MS: APCI(+ve) 438 (M+H).

(ii)3-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-6-methoxy-2,4(1H,3H)-quinazolinedione

The product of step (i) above was dissolved in toluene (10 ml). Asolution of phosgene 2.0 M in toluene (10 ml) was added, the solutionheated under reflux for 1 hour and cooled. Ethyl acetate and aqueousNaHCO₃ solution were added, the organic phase separated, dried andconcentrated to leave a residue which was purified by chromatography(dichloromethane:methanol, 95:5). The titled product was obtained as asolid (0.11 g).

MS: ESI 464.11 (M+H).

¹H NMR: δ(DMSO) 7.49 (dd, 1H), 7.36 (d, 1H), 7.30 (dd, 1H), 7.24 (d,1H), 6.98 (dd, 1H), 4.44 (m, 1H), 4.03 (t, 3H), 3.80 (s, 3H), 2.76 (m,2H), 2.32 (m, 2H), 1.89 (m, 2H), 1.57 (m, 2H).

Melting point: 190° C.

The compounds of following Examples 32 to 125 were prepared by methodsanalogous to the method of Example 10.

EXAMPLE 32N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-fluorobenzamide

MS: APC1 (+ve) BP 411.

EXAMPLE 33 N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}benzamide

MS: APC1 (+ve) BP 393.

EXAMPLE 344-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide

MS: APC1 (+ve) BP 429.

EXAMPLE 35N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-methoxybenzamide

MS: APC1 (+ve) BP 423.

EXAMPLE 36N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-methoxybenzamide

MS: APC1 (+ve) BP 423.

EXAMPLE 37N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-methoxybenzamide

MS: APC1 (+ve) BP 423.

EXAMPLE 38N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-nitrobenzamide

MS: APC1 (+ve) BP 438.

EXAMPLE 39N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-methylbenzamide

MS: APC1 (+ve) BP 407.

EXAMPLE 40N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-(trifluoromethyl)benzamide

MS: APC1 (+ve) BP 461.

EXAMPLE 41N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3,5-dinitrobenzamide

MS: APC1 (+ve) BP 483.

EXAMPLE 42N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-iodobenzamide

MS: APC1 (+ve) BP 519.

EXAMPLE 434-Cyano-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide

MS: APC1 (+ve) BP 418.

EXAMPLE 444-Bromo-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide

MS: APC1 (+ve) BP 473.

EXAMPLE 45N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-methylbenzamide

MS: APC1 (+ve) BP 407.

EXAMPLE 46N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-nitrobenzamide

MS: APC1 (+ve) BP 438.

EXAMPLE 473-Bromo-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide

MS: APC1 (+ve) BP 473.

EXAMPLE 483,4-Dichloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide

MS: APC1 (+ve) BP 463.

EXAMPLE 49N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-fluorobenzamide

MS: APC1 (+ve) BP 411.

EXAMPLE 502,4-Dichloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide

MS: APC1 (+ve) BP 463.

EXAMPLE 51N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-methylbenzamide

MS: APC1 (+ve) BP 407.

EXAMPLE 52N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-iodobenzamide

MS: APC1 (+ve) BP 519.

EXAMPLE 534-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-3-nitrobenzamide

MS: APC1 (+ve) BP 472.

EXAMPLE 54N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-methyl-3-nitrobenzamide

MS: APC1 (+ve) BP 452.

EXAMPLE 55N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-fluoro-5-(trifluoromethyl)benzamide

MS: APC1 (+ve) BP 479.

EXAMPLE 56N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-(trifluoromethoxy)benzamide

MS: APC1 (+ve) BP 477.

EXAMPLE 573,5-Dichloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide

MS: APC1 (+ve) BP 463.

EXAMPLE 58N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-(trifluoromethyl)benzamide

MS: APC1 (+ve) BP 461.

EXAMPLE 593-Cyano-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide

MS: APC1 (+ve) BP 418.

EXAMPLE 602-Bromo-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-5-methoxybenzamide

MS: APC1 (+ve) BP 503.

EXAMPLE 61 N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-furamide

MS: APC1 (+ve) BP 383.

EXAMPLE 623-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide

MS: APC1 (+ve) BP 427.

EXAMPLE 632-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide

MS: APC1 (+ve) BP 429.

EXAMPLE 64N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3,5-difluorobenzamide

MS: APC1 (+ve) BP 429.

EXAMPLE 652,3-Dichloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide

MS: APC1 (+ve) BP 463.

EXAMPLE 66N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-naphthamide

MS: APC1 (+ve) BP 442.

EXAMPLE 67N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(methylsulfanyl)nicotinamide

MS: APC1 (+ve) BP 440.

EXAMPLE 68N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-fluoro-6-(trifluoromethyl)benzamide

MS: APC1 (+ve) BP 479.

EXAMPLE 69N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2,4-difluorobenzamide

MS: APC1 (+ve) BP 429.

EXAMPLE 70N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-thiophenecarboxamide

MS: APC1 (+ve) BP 399.

EXAMPLE 71N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-quinoxalinecarboxamide

MS: APC1 (+ve) BP 445.

EXAMPLE 72 Methyl4-({2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}amino)-4-oxobutanoate

MS: APC1 (+ve) BP 403.

EXAMPLE 73N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}bicyclo[2.2.1]hept-5-ene-2-carboxamide

MS: APC1 (+ve) BP 409.

EXAMPLE 74N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}cyclobutanecarboxamide

MS: APC1 (+ve) BP 371.

EXAMPLE 75N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-methoxyacetamide

MS: APC1 (+ve) BP 361.

EXAMPLE 76N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}cyclohexanecarboxamide

MS: APC1 (+ve) BP 399.

EXAMPLE 77(E)-N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-phenyl-2-propenamide

MS: APC1 (+ve) BP 419.

EXAMPLE 782-Chloro-N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}nicotinamide

MS: APC1 (+ve) BP 430.

EXAMPLE 79N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-phenylacetamide

MS: APC1 (+ve) BP 407.

EXAMPLE 80N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}cyclopentanecarboxamide

MS: APC1 (+ve) BP 385.

EXAMPLE 81N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-phenoxyacetamide

MS: APC1 (+ve) BP 423.

EXAMPLE 82 N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}benzamide

MS: APC1 (+ve) BP 371.

EXAMPLE 83N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-(trifluoromethyl)benzamide

MS: APC1 (+ve) BP 439.

EXAMPLE 844-(tert-Butyl)-N-{2-[4-(4-chlorobenzoyl)-1-piperidinyl]ethyl}benzamide

MS: APC1 (+ve) BP 427.

EXAMPLE 85N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-4-methylbenzamide

MS: APC1 (+ve) BP 385.

EXAMPLE 86N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-4-nitrobenzamide

MS: APC1 (+ve) BP 416.

EXAMPLE 87N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-methylbenzamide

MS: APC1 (+ve) BP 385.

EXAMPLE 88N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-4-methyl-3-nitrobenzamide

MS: APC1 (+ve) BP 430.

EXAMPLE 89N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-cyanobenzamide

MS: APC1 (+ve) BP 396.

EXAMPLE 90 N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-furamide

MS: APC1 (+ve) BP 361.

EXAMPLE 91N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-nitrobenzamide

MS: APC1 (+ve) BP 416.

EXAMPLE 92 N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-naphthamide

MS: APC1 (+ve) BP 421.

EXAMPLE 93N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-(methylsulfanyl)nicotinamide

MS: APC1 (+ve) BP 418.

EXAMPLE 94N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-(2,3-dihydro-1,4-benzodioxin-2-2yl)-1,3-thiazole-4-carboxamide

MS: APC1 (+ve) BP 512.

EXAMPLE 95N˜2˜-Cyclopropyl-N˜4˜{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-2,4-pyrimidinediamine

MS: APCI(+ve) 422 (M+1).

EXAMPLE 962-{[4-({2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}amino)-2-pyrimidinyl]amino}-1-ethanol

MS: APCI(+ve) 426 (M+1).

EXAMPLE 972-[[4-({2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}amino)-2-pyrimidinyl](methyl)amino]-1-ethanol

MS: APCI(+ve) 440 (M+1).

EXAMPLE 98N˜4˜-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-N˜2˜-phenyl-2,4-pyrimidinediamine

MS: APCI(+ve) 458 (M+1).

EXAMPLE 99N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(methylsulfanyl)-4-pyrimidinamine

MS: APCI(+ve) 413 (M+1).

EXAMPLE 100N˜4˜-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-6-methyl-2,4-pyrimidinediamine

MS: APCI(+ve) 396 (M+1).

EXAMPLE 101N˜4˜-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-N˜2˜,6-dimethyl-2,4-pyrimidinediamine

MS: APCI(+ve) 410 (M+1).

EXAMPLE 1022-Chloro-N˜4˜-cyclopropyl-N˜6˜-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-4,6-pyrimidinediamine

MS: APCI(+ve) 456 (M+1).

EXAMPLE 103N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-phenyl-2-pyrimidinamine

MS: APCI(+ve) 443 (M+1).

EXAMPLE 104N˜2˜-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-N˜4˜,N˜4˜,6-trimethyl-2,4-pyrimidinediamine

MS: APCI(+ve) 424 (M+1).

EXAMPLE 105N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-(trifluoromethyl)-2-pyrimidinamine

MS: APCI(+ve) 435 (M+1).

EXAMPLE 106N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-(propylsulfanyl)-2-pyrimidinamnine

MS: APCI(+ve) 441 (M+1).

EXAMPLE 107N˜2˜-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-N˜4˜-phenyl-2,4-pyrimidinediamine

MS: APCI(+ve) 458 (M+1).

EXAMPLE 108N˜4˜-Cyclopropyl-N˜2˜-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-2,4-pyrimidinediamine

MS: APCI(+ve) 422 (M+1).

EXAMPLE 109N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}[1,8]naphthyridin-2-amine

MS: APCI(+ve) 417 (M+1).

EXAMPLE 110N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-(3-pyridinyl)-2-pyrimidinamine

MS: APCI(+ve) 444 (M+1).

EXAMPLE 111N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-pyrimidinamine

MS: APCI(+ve) 367 (M+1).

EXAMPLE 112N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4,6-dimethoxy-2-pyrimidinamine

MS: APCI(+ve) 427 (M+1).

EXAMPLE 113N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-(3-furyl)-2-pyrimidinamine

MS: APCI(+ve) 433 (M+1).

EXAMPLE 114N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

MS: APCI(+ve) 421 (M+1).

EXAMPLE 115N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-1H-purin-6-amine

MS: APCI(+ve) 407 (M+1).

EXAMPLE 116N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-5-methylthieno[2,3-d]pyrimidin-4-amine

MS: APCI(+ve) 437 (M+1).

EXAMPLE 117N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-7-methylthieno[3,2-d]pyrimidin-4-amine

MS: APCI(+ve) 437 (M+1).

EXAMPLE 118N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-thiophenecarboxamide

MS: APC1 (+ve) BP 377.

EXAMPLE 119N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-quinoxalinecarboxamide

MS: APC1 (+ve) BP 423.

EXAMPLE 120N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}bicyclo[2.2.1]hept-5-ene-2-carboxamide

MS: APC1 (+ve) BP 387.

EXAMPLE 121N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}cyclohexanecarboxamide

MS: APC1 (+ve) BP 377.

EXAMPLE 122(E)-N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-phenyl-2-propenamide

MS: APC1 (+ve) BP 397.

EXAMPLE 123N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-phenoxyacetamide

MS: APC1 (+ve) BP 401.

EXAMPLE 124(E)-N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-(4-nitrophenyl)-2-propenamide

MS: APC1 (+ve) BP 442.

EXAMPLE 1252-(1-Adamantyl)-N-{2-[4-(4-chlorobenzoyl)-1-piperidinyl]ethyl}acetamide

MS: APC1 (+ve) BP 443.

The compounds of following Examples 126 to 168 were prepared by methodsanalogous to the method of Example 30.

EXAMPLE 126(4-Chlorophenyl)(1-{2-[(2-fluoro-4,5-dimethoxybenzyl)amino]ethyl}-4-piperidinyl)methanone

MS: APC1 (+ve) BP 435.

EXAMPLE 127(4-Chlorophenyl)(1-{2-[(3,4,5-trimethoxybenzyl)amino]ethyl}-4-piperidinyl)methanone

MS: APC1 (+ve) BP 447.

EXAMPLE 128(4-Chlorophenyl)(1-{2-[(3-nitrobenzyl)amino]ethyl}-4-piperidinyl)methanone

MS: APC1 (+ve) BP 402.

EXAMPLE 129(4-Chlorophenyl){1-[2-(isobutylamino)ethyl]-4-piperidinyl}methanone

MS: APC1 (+ve) BP 323.

EXAMPLE 1304-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}amino)methyl]-4-ethylhexanenitrile

MS: APC1 (+ve) BP 404.

EXAMPLE 131(4-Chlorophenyl)(1-{2-[(7-hydroxy-3,7-dimethyloctyl)amino]ethyl}-4-piperidinyl)methanone

MS: APC1 (+ve) BP 423.

EXAMPLE 132(4-Chlorophenyl)[1-(2-{[(6-nitro-1,3-benzodioxol-5-yl)methyl]amino}ethyl)-4-piperidinyl]methanone

MS: APC1 (+ve) BP 446.

EXAMPLE 133[1-(2-{[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl]amino}ethyl)-4-piperidinyl](4-chlorophenyl)methanone

MS: APC1 (+ve) BP 409.

EXAMPLE 134(4-Chlorophenyl)[1-(2-{[3-nitro-4-(2-pyridinylsulfanyl)benzyl]amino}ethyl)-4-piperidinyl]methanone

MS: APC1 (+ve) BP 511.

EXAMPLE 135(4-Chlorophenyl)[1-(2-{[(E)-3-(4-nitrophenyl)-2-propenyl]amino}ethyl)-4-piperidinyl]methanone

MS: APC1 (+ve) BP 428.

EXAMPLE 136(4-Chlorophenyl){1-[2-({[5-(3-nitrophenyl)-2-furyl]methyl}amino)ethyl]-4-piperidinyl}methanone

MS: APC1 (+ve) BP 468.

EXAMPLE 137(4-Chlorophenyl)[1-(2-{[5-nitro-2-(2-pyridinylsulfanyl)benzyl]amino}ethyl)-4-piperidinyl]methanone

MS: APC1 (+ve) BP 511.

EXAMPLE 1386-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}amino)methyl]-2-(methylsulfanyl)nicotinonitrile

MS: APC1 (+ve) BP 429.

EXAMPLE 139{1-[2-({[5-Chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}amino)ethyl]-4-piperidinyl}(4-chlorophenyl)methanone

MS: APC1 (+ve) BP 463.

EXAMPLE 140(4-Chlorophenyl)[1-(2-{[3-(methylsulfanyl)butyl]amino}ethyl)4-piperidinyl]methanone

MS: APC1 (+ve) BP 369.

EXAMPLE 141(4-Chlorophenyl)[1-(2-{[(4-phenyl-4-piperidinyl)methyl]amino}ethyl)-4-piperidinyl]methanone

MS: APC1 (+ve) BP 440.

EXAMPLE 142(4-Chlorophenyl)[1-(2-{[(1-phenyl-1H-pyrazol-5-yl)methyl]amino}ethyl)-4-piperidinyl]methanone

MS: APC1 (+ve) BP 423.

EXAMPLE 143 Ethyl3-[({2-[4-(4-chlorobenzoyl)-1-piperidinyl]ethyl}-amino)methyl]cyclohexanecarboxylate

MS: APC1 (+ve) BP 435.

EXAMPLE 144N-{4-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}amino)methyl]phenyl}acetamide

MS: APC1 (+ve) BP 414.

EXAMPLE 145(4-Chlorophenyl)(1-{2-[(2,5-difluorobenzyl)amino]ethyl}-4-piperidinyl)methanone

MS: APC1 (+ve) BP 393.

EXAMPLE 146(4-Chlorophenyl)(1-{2-[(4-nitrobenzyl)amino]ethyl}-4-piperidinyl)methanone

MS: APC1 (+ve) BP 402.

EXAMPLE 147(4-Chlorophenyl)(1-{2-[(2,6-dichlorobenzyl)amino]ethyl}-4-piperidinyl)methanone

MS: APC1 (+ve) BP 425.

EXAMPLE 148(4-Chlorophenyl)(1-{2-[(2-pyridinylmethyl)amino]ethyl}-4-piperidinyl)methanone

MS: APC1 (+ve) BP 358.

EXAMPLE 149(4-Chlorophenyl)[1-(2-{[(3-methyl-2-thienyl)methyl]amino}ethyl)-4-piperidinyl]methanone

MS: APC1 (+ve) BP 377.

EXAMPLE 150(4-Chlorophenyl)(1-{2-[(3-hydroxy-4-methoxybenzyl)amino]ethyl}-4-piperidinyl)methanone

MS: APC1 (+ve) BP 403.

EXAMPLE 1513-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}amino)methyl]-4H-chromen-4-one

MS: APC1 (+ve) BP 425.

EXAMPLE 152[1-(2-{[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl]amino}ethyl)-4-piperidinyl](4-chlorophenyl)methanone

MS: APC1 (+ve) BP 409.

EXAMPLE 153(4-Chlorophenyl)[1-(2-{[(2,6-dichloro-4-pyridinyl)methyl]amino}ethyl)-4-piperidinyl]methanone

MS: APC1 (+ve) BP 428.

EXAMPLE 154(4-Chlorophenyl)[1-(2-{[(2-phenyl-1H-imidazol-4-yl)methyl]amino}ethyl)-4-piperidinyl]methanone

MS: APC1 (+ve) BP 423.

EXAMPLE 155(4-Chlorophenyl)[1-(2-{[(5-ethyl-2-thienyl)methyl]amino}ethyl)-4-piperidinyl]methanone

MS: APC1 (+ve) BP 391.

EXAMPLE 156(4-Chlorophenyl)[1-(2-{[(2-chloro-3-quinolinyl)methyl]amino}ethyl)-4-piperidinyl]methanone

MS: APC1 (+ve) BP 442.

EXAMPLE 157(4-Chlorophenyl)[1-(2-{[(6-methyl-2-pyridinyl)methyl]amino}ethyl)-4-piperidinyl]methanone

MS: APC1 (+ve) BP 372.

EXAMPLE 158(4-Chlorophenyl)(1-{2-[(3-quinolinylmethyl)amino]ethyl}-4-piperidinyl)methanone

MS: APC1 (+ve) BP 408.

EXAMPLE 1594-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}amino)methyl]-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one

MS: APC1 (+ve) BP 467.

EXAMPLE 160(4-Chlorophenyl)(1-{2-[(4-pyridinylmethyl)amino]ethyl}-4-piperidinyl)methanone

MS: APC1 (+ve) BP 358.

EXAMPLE 161(4-Chlorophenyl)(1-{2-[(3-hydroxy-4-nitrobenzyl)amino]ethyl}-4-piperidinyl)methanone

MS: APC1 (+ve) BP 418.

EXAMPLE 162(4-Chlorophenyl)(1-{2-[(3,5-difluorobenzyl)amino]ethyl}-4-piperidinyl)methanone

MS: APC1 (+ve) BP 393.

EXAMPLE 163(1-{2-[(2-Chloro-6-fluorobenzyl)amino]ethyl}-4-piperidinyl)(4-chlorophenyl)methanone

MS: APC1 (+ve) BP 409.

EXAMPLE 164[1-(2-{[(4-Bromo-1H-pyrazol-3-yl)methyl]amino}ethyl)4-piperidinyl](4-chlorophenyl)methanone

MS: APC1 (+ve) BP 427.

EXAMPLE 1653-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}amino)methyl]-6,7-dimethyl-4H-chromen-4-one

MS: APC1 (+ve) BP 453.

EXAMPLE 1662-{2-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}amino)methyl]-4-nitrophenoxy}aceticacid

MS: APC1 (+ve) BP 476.

EXAMPLE 167(4-Chlorophenyl)[1-(2-{[(1-methyl-1H-benzimidazol-2-yl)methyl]amino}ethyl)-4-piperidinyl]methanone

MS: APC1 (+ve) BP 411.

EXAMPLE 168(4-Chlorophenyl)[1-(2-{[(2,4-dimethoxy-5-pyrimidinyl)methyl]amino}ethyl)-4-piperidinyl]methanone

MS: APC1 (+ve) BP 419.

The compounds of following Examples 169 to 209 were prepared by methodsanalogous to the method of Example 2.

EXAMPLE 169N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-(methylamino)benzamide

MS: APC1 (+ve) BP 422.

EXAMPLE 1704-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-3-methoxybenzamide

MS: APC1 (+ve) BP 459.

EXAMPLE 171N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-methoxy-4-methylbenzamide

MS: APC1 (+ve) BP 437.

EXAMPLE 1723-Amino-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-4-methoxybenzamide

MS: APC1 (+ve) BP 438.

EXAMPLE 173N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-1,3-benzodioxole-5-carboxamide

MS: APC1 (+ve) BP 437.

EXAMPLE 1744-Amino-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-3-methoxybenzamide

MS: APC1 (+ve) BP 438.

EXAMPLE 175N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-fluoro-4-methoxybenzamide

MS: APC1 (+ve) BP 441.

EXAMPLE 1765-Bromo-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-2-furamide

MS: APC1 (+ve) BP 463.

EXAMPLE 177N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-methyl-2-furamide

MS: APC1 (+ve) BP 397.

EXAMPLE 178N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4,5-dimethyl-2-furamide

MS: APC1 (+ve) BP 411.

EXAMPLE 179N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-7-ethoxy-1-benzofuran-2-carboxamide

MS: APC1 (+ve) BP 477.

EXAMPLE 180N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-5-methoxy-1-benzofuran-2-carboxamide

MS: APC1 (+ve) BP 463.

EXAMPLE 181N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-7-methoxy-1-benzofuran-2-carboxamide

MS: APC1 (+ve) BP463.

EXAMPLE 182N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(4-fluorophenyl)acetamide

MS: APC1 (+ve) BP 425.

EXAMPLE 183N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(2-methoxyphenyl)acetamide

MS: APC1 (+ve) BP 437.

EXAMPLE 184N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(3-methylphenyl)acetamide

MS: APC1 (+ve) BP421.

EXAMPLE 185N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(2-methylphenyl)acetamide

MS: APC1 (+ve) BP 421.

EXAMPLE 1862-(3-Bromophenyl)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}acetamide

MS: APC1 (+ve) BP 487.

EXAMPLE 1872-(2-Chlorophenyl)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}acetamide

MS: APC1 (+ve) BP 441.

EXAMPLE 1882-(4-Chlorophenyl)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}acetamide

MS: APC1 (+ve) BP 443.

EXAMPLE 189N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-[2-(trifluoromethyl)phenyl]acetamide

MS: APC1 (+ve) BP 475.

EXAMPLE 1902-(3-Chlorophenyl)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}acetamide

MS: APC1 (+ve) BP441.

EXAMPLE 191N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(3,4-dimethoxyphenyl)acetamide

MS: APC1 (+ve) BP467.

EXAMPLE 192N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(4-methoxyphenyl)acetamide

MS: APC1 (+ve) BP 437.

EXAMPLE 193N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(3,4-dichlorophenyl)acetamide

MS: APC1 (+ve) BP 477.

EXAMPLE 194N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(3-fluoro-4-methoxyphenyl)acetamide

MS: APC1 (+ve) BP 455.

EXAMPLE 195N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(4-ethoxyphenyl)acetamide

MS: APC1 (+ve) BP 451.

EXAMPLE 1962-(1,3-Benzodioxol-5-yl)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}acetamide

MS: APC1 (+ve) BP451.

EXAMPLE 197N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-[4-(dimethylamino)phenyl]acetamide

MS: APC1 (+ve) BP 450.

EXAMPLE 198N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(4-methylphenyl)acetamide

MS: APC1 (+ve) BP 421.

EXAMPLE 199N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(3,4-difluorophenyl)acetamide

MS: APC1 (+ve) BP 443.

EXAMPLE 200N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(3-methoxyphenyl)acetamide

MS: APC1 (+ve) BP 437.

EXAMPLE 201N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-phenylbutanamide

MS: APC1 (+ve) BP 435.

EXAMPLE 202N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-phenylpropanamide

MS: APC1 (+ve) BP 421.

EXAMPLE 203N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-(3-methoxyphenyl)propanamide

MS: APC1 (+ve) BP 451.

EXAMPLE 2042-Amino-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-1,3-thiazole-4-carboxamide

MS: APC1 (+ve) BP 416.

EXAMPLE 2052-(Acetylamino)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-1,3-thiazole-4-carboxamide

MS: APC1 (+ve) BP 457.

EXAMPLE 206N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(4-pyridinyl)-1,3-thiazole-4-carboxamide

MS: APC1 (+ve) BP 477.

EXAMPLE 207N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2,4-dimethyl-1,3-thiazole-5-carboxamide

MS: APC1 (+ve) BP 428.

EXAMPLE 208N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2,5-dimethyl-1,3-oxazole-4-carboxamide

MS: APC1 (+ve) BP 412.

EXAMPLE 209N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-1H-imidazole-4-carboxamide

MS: APC1 (+ve) BP 385.

EXAMPLE 210N-{2-[4-(3,4-Chlorophenoxy)-1-piperidinyl]ethyl}-3-methoxybenzamidehydrochloride

(i) 2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethylamine trifluoroacetate

Prepared by the method of Example 1 steps (i) to (iv) using3-chlorophenol to give the product as an oil (0.5 g) which was useddirectly in the next step without further purification.

(ii) N-{2-[4-(3,4-Chlorophenoxy)-1-piperidinyl]ethyl}-3-methoxybenzamidehydrochloride

The product of step (i) above (0.3 g) was dissolved in dichloromethane(490 ml), triethylamine (4 equiv) and 3-methoxybenzoyl chloride (1equiv) were added. After 72 hours at room temperature, water was added,the organic phase separated, dried and concentrated to a gum. Theproduct was dissolved in dichloromethane and treated with 1.0M etherealhydrogen chloride solution to give the titled product as a solid (0.1g).

Melting point: 175-176° C.

MS: APCI(+ve): 389 (M+H).

¹H NMR: δ(DMSO) 8.87 (t, 1H), 7.5 (m, 2H), 7.42 (m, 1H), 7.32 (m, 1H),7.13 (m, 2H), 6.98 (m, 2H), 4.82 (m, 1/2H), 4.61 (m, 1/2H), 3.81 (s,3H), 3.69 (m, 3H), 3.68 (m, 3H), 3.47 (m, 1H), 3.13-3.22 (m, 4H), 2.27(m, 1H), 2.14 (m, 1H), 2.03 (m, 1H), 1.90 (m, 1H).

EXAMPLE 211N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

(i)2-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-1H-isoindole-1,3(2H)-dione

A solution of the product from Example 1 step (ii) (2.0 g),2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione (1.61 g) and triethylamine(2.5 ml) in dichloromethane (40 ml) was heated under reflux for 48 h.The reaction mixture was partitioned between ethyl acetate/water, theorganic layer dried and evaporated under reduced pressure. Purificationwas by chromatography eluting with 4% methanol/dichloromethane. Yield0.839 g

MS: APCI(+ve) 433 (M+1).

(ii) 3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propylamine,dihydrochloride salt

The product from step (i) (0.83 g) and hydrazine hydrate (0.1 ml) inethanol was heated under reflux for 6 h. The precipitate was filteredoff and partitioned between 2M hydrochloric acid and dichloromethane,the solid was filtered off and the aqueous layer basified with aqueouspotassium hydroxide solution and extracted with dichloromethane. Theorganic layer was dried, evaporated under reduced pressure and thedihydrochloride salt formed using ethereal hydrogen chloride. Yield 0.28g

¹H NMR: δ(DMSO-d₆) 11.11 (br s, 1H), 8.13 (br s, 3H), 7.56 (d, 1H), 7.37(s, 1H), 7.10-7.06 (br m, 1H), 4.84 (br s, 0.5H), 4.65 (br s, 0.5H),3.60-2.90 (m, 8H), 2.24-2.01 (m, 6H).

(iii)N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

The product from step (ii) (0.08 g),4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (0.054 g) anddiisopropylethylamine (0.082 g) in 1-methyl-2-pyrrolidinone (2 ml) washeated at 50° C. for 3 h. The reaction mixture was diluted with ethylacetate and washed with water. The organic layer was dried and thesolvent removed under reduced pressure. Purification was bychromatography eluting with 9% methanol/dichloromethane. Yield 0.052 g

MS: APCI(+ve) 435 (M+1).

¹H NMR: δ(DMSO-d₆) 8.25-8.22 (m, 2H), 8.07 (s, 1H), 7.49 (d, 1H), 7.25(d, 1H), 6.9 (dd, 1H), 4.46-4.42 (m, 1H), 3.88 (s, 3H), 3.49 (q, 2H),2.70-2.66 (m, 2H), 2.40-2.36 (m, 2H), 2.27-2.22 (m, 2H), 1.92-1.88 (m,2H), 1.81-1.74 (m, 2H), 1.62-1.59 (m, 2H).

Melting point: 120-124° C.

EXAMPLES 212-255

The product from Example 211 step (ii) (1.5 mg), the appropriateactivated halo aromatic (1.25 equivalents), diisopropylethylamine (10equivalents) in 1-methyl-2-pyrrolidinone (0.15 ml) were heated at 100°C. for 24 h. The reaction mixture was evaporated to dryness and theresidue dissolved in dimethylsulphoxide (0.4 ml).

EXAMPLE 212N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2,6-dimethoxy-4-pyrimidinamine

MS: APCI(+ve) 441 (M+1).

EXAMPLE 213N˜4˜-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-N˜2˜,N˜2˜-dimethyl-2,4-pyrimidinediamine

MS: APCI(+ve) 424 (M+1).

EXAMPLE 214N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-[(methylsulfanyl)methyl]-4-pyrimidinamine

MS: APCI(+ve) 441 (M+1).

EXAMPLE 215N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-(methylsulfanyl)-6-(trifluoromethyl)-4-pyrimidinamine

MS: APCI(+ve) 495 (M+1).

EXAMPLE 216N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-5-methoxy-2-(methylsulfanyl)-4-pyrimidinamine

MS: APCI(+ve) 457 (M+1).

EXAMPLE 217N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-6-methyl-2-(methylsulfanyl)-4-pyrimidinamine

MS: APCI(+ve) 441 (M+1).

EXAMPLE 218N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-5-methoxy-2-methyl-4-pyrimidinamine

MS: APCI(+ve) 425 (M+1).

EXAMPLE 219N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-(ethylsulfanyl)-6-methyl-4-pyrimidinamine

MS: APCI(+ve) 455 (M+1).

EXAMPLE 220N˜2˜-Cyclopropyl-N˜4˜-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]propyl}-2,4-pyrimidinediamine

MS: APCI(+ve) 436 (M+1).

EXAMPLE 2212-{[4-({3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}amino)-2-pyrimidinyl]amino}-1-ethanol

MS: APCI(+ve) 440 (M+1).

EXAMPLE 2222-[[4-({3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl[propyl}amino)-2-pyrimidinyl](methyl)amino]-1-ethanol

MS: APCI(+ve) 454 (M+1).

EXAMPLE 223N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-(methylsulfanyl)-4-pyrimidinamine

MS: APCI(+ve) 427 (M+1).

EXAMPLE 224N˜4˜-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-6-methyl-2,4-pyrimidinediamine

MS: APCI(+ve) 410 (M+1).

EXAMPLE 225N˜4˜-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-N˜2˜,6-dimethyl-2,4-pyrimidinediamine

MS: APCI(+ve) 424 (M+1).

EXAMPLE 226N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-phenyl-2-pyrimidinamine

MS: APCI(+ve) 457 (M+1).

EXAMPLE 227N˜2˜-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-5-fluoro-2,4-pyrimidinediamine

MS: APCI(+ve) 414 (M+1).

EXAMPLE 228N˜2˜-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-N˜4˜,N˜4˜,6-trimethyl-2,4-pyrimidinediamine

MS: APCI(+ve) 438 (M+1).

EXAMPLE 229N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-(trifluoromethyl)-2-pyrimidinamine

MS: APCI(+ve) 449 (M+1).

EXAMPLE 230N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-(propylsulfanyl)-2-pyrimidinamine

MS: APCI(+ve) 455 (M+1).

EXAMPLE 231N˜2˜-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-N˜4˜-phenyl-2,4-pyrimidinediamine

MS: APCI(+ve) 472 (M+1).

EXAMPLE 232N˜2˜-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-N˜4˜,6-dimethyl-2,4-pyrimidinediamine

MS: APCI(+ve) 424 (M+1).

EXAMPLE 233N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}[1,8]naphthyridin-2-amine

MS: APCI(+ve) 431 (M+1).

EXAMPLE 2342-{[2-({3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}amino)-4-pyrimidinyl]amino}-1-ethanol

MS: APCI(+ve) 440 (M+1).

EXAMPLE 2352-[[2-({3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}amino)-4-pyrimidinyl](methyl)amino]-1-ethanol

MS: APCI(+ve) 454 (M+1).

EXAMPLE 236N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-(3-pyridinyl)-2-pyrimidinamine

MS: APCI(+ve) 45 (M+1).

EXAMPLE 237N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-(3-thienyl)-2-pyrimidinamine

MS: APCI(+ve) 463 (M+1).

EXAMPLE 238N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-pyrimidinamine

MS: APCI(+ve) 381 (M+1).

EXAMPLE 239N-{3-[4-3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4,6-dimethoxy-2-pyrimidinamine

MS: APCI(+ve) 441 (M+1).

EXAMPLE 240N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-(3-furyl)-2-pyrimidinamine

MS: APCI(+ve) 447 (M+1).

EXAMPLE 241N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-(2-thienyl)-2-pyrimidinamine

MS: APCI(+ve) 463 (M+1).

EXAMPLE 242N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-1H-purin-6-amine

MS: APCI(+ve) 421 (M+1).

EXAMPLE 243N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-5-methylthieno[2,3-d]pyrimidin-4-amine

MS: APCI(+ve) 451 (M+1).

EXAMPLE 244N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-7-methylthieno[3,2-d]pyrimidin-4-amine

MS: APCI(+ve) 451 (M+1).

EXAMPLE 245N˜7˜-{3-[4-(3,4Dichlorophenoxy)-1-piperidinyl]propyl}-5-methyl[1,3]thiazolo[4,5-d]pyrimidine-2,7-diamine

MS: APCI(+ve) 467 (M+1).

EXAMPLE 246N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-9-methyl-9H-purin-6-amine

MS: APCI(+ve) 435 (M+1).

EXAMPLE 247N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-pyridinamine

MS: APCI(+ve) 379 (M+1).

EXAMPLE 2485-Chloro-N-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]propyl}-2-pyridinamine

MS: APCI(+ve) 414 (M+1).

EXAMPLE 2496-Chloro-N-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]propyl}-2-pyridinamine

MS: APCI(+ve) 414 (M+1).

EXAMPLE 250N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-6-methyl-2-pyridinamine

MS: APCI(+ve) 494 (M+1).

EXAMPLE 251N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-1,3-benzothiazol-2-amine

MS: APCI(+ve) 436 (M+1).

EXAMPLE 252N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-1,3-benzoxazol-2-amine

MS: APCI(+ve) 420 (M+1).

EXAMPLE 2536-Chloro-N-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]propyl}-2-pyrazinamine

MS: APCI(+ve) 415 (M+1).

EXAMPLE 2546-Chloro-N-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]propyl}-3-pyridazinamine

MS: APCI(+ve) 417 (M+1).

EXAMPLE 2556-({3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}amino)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione

MS: APCI(+ve) 441 (M+1).

EXAMPLES 256-292

The product from Example 1 step (iv) (2.07 mg), the appropriateactivated halo aromatic (1.25 equivalents), diisopropylethylamine (10equivalents) in 1-methyl-2-pyrrolidinone (0.15 ml) were heated at 100°C. for 24 h. The reaction mixture was evaporated to dryness and theresidue dissolved in dimethylsulphoxide (0.4 ml).

EXAMPLE 256N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2,6-dimethoxy-4-pyrimidinamine

MS: APCI(+ve) 427 (M+1).

EXAMPLE 257N˜4˜-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-N˜2˜,N˜2˜-dimethyl-2,4-pyrimidinediamine

MS: APCI(+ve) 410 (M+1).

EXAMPLE 258N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-[(methylsulfanyl)methyl]-4-pyrimidinamine

MS: APCI(+ve) 427 (M+1).

EXAMPLE 259N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-5-methoxy-2-(methylsulfanyl)-4-pyrimidinamine

MS: APCI(+ve) 443 (M+1).

EXAMPLE 260N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-6-methyl-2-(methylsulfanyl)-4-pyrimidinamine

MS: APCI(+ve) 427 (M+1).

EXAMPLE 261N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-5-methoxy-2-methyl-4-pyrimidinamine

MS: APCI(+ve) 411 (M+1).

EXAMPLE 262N˜4˜-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-6-methyl-N˜2˜-phenyl-2,4-pyrimidinediamine

MS: APCI(+ve) 472 (M+1).

Pharmacological Analysis

Calcium flux [Ca²⁺]_(i) assay

a) Human Eosinophils

Human eosinophils were isolated from EDTA anticoagulated peripheralblood as previously described (Hansel et al., J. Immunol. Methods, 1991,145, 105-110). The cells were resuspended (5×10⁶ ml⁻¹) and loaded with 5μM FLUO-3/AM+Pluronic F127 2.2 μl/ml (Molecular Probes) in low potassiumsolution (LKS; NaCl 118 mM, MgSO₄ 0.8 mM, glucose 5.5 mM, Na₂CO₃ 8.5 mM,KCl 5 mM, HEPES 20 mM, CaCl₂ 1.8 mM, BSA 0.1%, pH 7.4) for one hour atroom temperature. After loading, cells were centrifuged at 200 g for 5min and resuspended in LKS at 2.5×10⁶ ml⁻¹. The cells were thentransferred to 96 well FLIPr plates (Poly-D-Lysine plates from BectonDickinson pre-incubated with 5 μM fibronectin for two hours) at 100ml/well. The plate was centrifuged at 200 g for 5 min and the cells werewashed twice with LKS (200 μl; room temperature).

A compound of the Examples was pre-dissolved in DMSO and added to afinal concentration of 0.1% (v/v) DMSO. Assays were initiated by theaddition of an A₅₀ concentration of eotaxin and the transient increasein fluo-3 fluorescence (I_(Ex)=490 nm and I_(Em)=520 nm) monitored usinga FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices,Sunnyvale, U.S.A.).

b) Human Monocytes

Human monocytes were isolated from EDTA anticoagulated peripheral bloodas previously described (Cunoosamy & Holbrook, J. Leukocyte Biology,1998, S2, 13). Cells were resuspended (5×10⁶ ml⁻¹) in LKS and loadedwith 5 μM FLUO-3/AM+Pluronic F127 2.2 μl/ml (Molecular Probes) for onehour at room temperature. After loading, cells were centrifuged at 200 gfor 5 min and resuspended in LKS at 0.5×10⁶ ml⁻¹. The cells were thentransferred to 96 well FLIPr plates (Costar). To each well 100 μl ofcells were added at a concentration of 0.5×10⁶ ml⁻¹. The plates werecentrifuged (200 g; 5 mins; room temperature) to allow the cells toadhere. After centrifugation the cells were washed twice with LKS (200μl; room temperature).

A compound of the Examples was pre-dissolved in DMSO and added to afinal concentration of 0.1% (v/v) DMSO. Assays were initiated by theaddition of an A₅₀ concentration of MIP-1α and the transient increase influo-3 fluorescence (I_(Ex)=490 nm and I_(Em)=520 nm) monitored using aFLIPR (Fluorometric Imaging Plate Reader, Molecular Devices, Sunnyvale,U.S.A.).

The compounds of the Examples were found to be antagonists of theeotaxin mediated [Ca²⁺]_(i) in human eosinophils and/or antagonists ofthe MIP-1α mediated [Ca²⁺]_(i) in human monocytes.

Human Eosinophil Chemotaxis

Human eosinophils were isolated from EDTA anticoagulated peripheralblood as previously described (Hansel et al., J. Immunol. Methods, 1991,145, 105-110). The cells were resuspended at 10×10⁶ ml⁻¹ in RPMIcontaining 200 IU/ml penicillin, 200 μg/ml streptomycin sulphate andsupplemented with 10% HIFCS, at room temperature.

Eosinophils (700 μl) were pre-incubated for 15 mins at 37° C. with 7 μlof either vehicle or compound (100× required final concentration in 10%DMSO). The chemotaxis plate (ChemoTx, 3 μm pore, Neuroprobe) was loadedby adding 28 μl of a concentration of eotaxin (0.1 to 100 nM) containinga concentration of a compound according to the Examples or solvent tothe lower wells of the chemotaxis plate. The filter was then placed overthe wells and 25 μl of eosinophil suspension were added to the top ofthe filter. The plate was incubated for 1 hr at 37° C. in a humidifiedincubator with a 95% air/5% CO₂ atmosphere to allow chemotaxis.

The medium, containing cells that had not migrated, was carefullyaspirated from above the filter and discarded. The filter was washedonce with phosphate buffered saline (PBS) containing 5 mM EDTA to removeany adherent cells. Cells that had migrated through the filter werepelleted by centrifugation (300×g for 5 mins at room temperature) andthe filter removed and the supernatant transferred to each well of a96-well plate (Costar). The pelleted cells were lysed by the addition of28 μl of PBS containing 0.5% Triton ×100 followed by two cycles offreeze/thawing. The cell lysate was then added to the supernatant. Thenumber of eosinophils migrating was quantified according to the methodof Strath et al., J. Immunol. Methods, 1985, 83, 209 by measuringeosinophil peroxidase activity in the supernatant.

Certain compounds of the Examples were found to be antagonists of theeotaxin mediated human eosinophil chemotaxis.

1. A compound of general formula

wherein: R¹ represents a 3- to 10-membered saturated or unsaturatedmonocyclic ring system containing up to two ring carbon atoms that formcarbonyl groups and which comprises 1,2,3 or 4 ring heteroatomsindependently selected from nitrogen, oxygen and sulfur, the ring systembeing optionally substituted by one or more substituents independentlyselected from halogen atoms, and cyano, nitro, hydroxyl, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxycarbonyl, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, —NR⁵R⁶, C₃-C₆ cycloalkylamido, C₁-C₆ alkylthio, C₁-C₆alkylthio C₁-C₆ alkyl, C₁-C₆ alkylcarbonylamino, —C(O)NR⁷R⁸,sulphonamido, (di)C₁-C₆ alkylsulphonamido, phenyl, phenylamino,nitrophenyl, pyridyl, pyridylthio, benzodioxanyl, thienyl, furanyl, andC(O)R⁹-substitutcd C₁-C₆ alkyl or C₁-C₆ alkoxy groups; m is 0 or 1; Qrepresents a group OCH₂, C₁-C₆ alkylene or C₂-C₄ alkenylene; Trepresents a group C(O)NH, or when m is 0 and R¹ is not optionallysubstituted pyridinyl then T may additionally be NH, or when m is 1 andQ is C₁-C₄ alkylene then T may additionally be NH; n is 1,2,3 or 4; eachR² independently represents a hydrogen atom or a C₁-C₄ alkyl group; eachR³ independently represents a hydrogen atom or a C₁-C₄ alkyl group; Vrepresents a nitrogen atom; W represents CH; X represents an oxygen atomor a group C(O), CH(OH), NH or N(C₁-C₆ alkyl); R⁴ represents a phenylgroup optionally substituted by one or more substituents independentlyselected from halogen atoms, and amino, nitro, cyano, sulphonyl,sulphonamido, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy and C₁-C₆alkylsulphonyl groups; R⁵ and R⁶ each independently represent a hydrogenatom or a C₂-C₆ alkyl or hydroxy C₁-C₆ alkyl group, or R⁵ and R⁶together with the nitrogen atom to which they are attached form a 4- to7-membered saturated heterocyclic ring; R⁷ and R⁸ each independentlyrepresent a hydrogen atom or a C₁-C₆ alkyl group; and R⁹ represents ahydroxyl or —NR⁷R⁸ group; with the provisions that (a) when m is 0, T isCONH, n is 2, 3 or 4 and each R² and R³ represents hydrogen, W is CH, Xis C(O) or CH(OH) and R¹ represents a substituted 3- to 10-memberedunsaturated ring system, then the one or more substituents in the ringsystem do not include hydroxyl, halogen, C₁-C₆ alkoxy or C₁-C₆haloalkoxy, and (b) when X is O, n is 2 or 3 and each R² and R³represents hydrogen, m is 0 and T is NH, then R¹ does not represent agroup

or a pharmaceutically acceptable salt or solvate thereof.
 2. A compoundaccording to claim 1, wherein R¹ represents a 3- to 10-memberedsaturated or unsaturated ring system comprising up to two ring carbonatoms that form carbonyl groups and comprising up to 4 ring heteroatomsindpendently selected from nitrogen, oxygen and sulfur, the ring systembeing optionally substituted by one, two or three substituentsindependently selected from halogen atoms, and cyano, nitro, hydroxyl,C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄, alkoxy, C₁-C₄ alkoxycarbonyl,C₁-C₃ haloalkyl, C₁-C₃ haloalkoxy, —NR⁵R⁶, C₃-C₆ cycloalkylamino, C₁-C₄alkylthio, C₁-C₄ alkylthio C₁-C₄ alkyl, C₁-C₄ alkylcarbonylammno,—C(O)NR⁷R⁸, phenyl, phenylamino, notrophenyl, pyridyl, pyridylthio,benzodiaxanyl, thienyl, furanyl and C(O)R⁹-substituted C₁-C₄ alkyl orC₁-C₄ groups.
 3. A compound according to claim 1 or claim 2, wherein mis 1 and Q represents a group OCH₂, C₁-C₃ alkylene or C₂-C₃ alkenylene.4. A compound according to claim 1 or claim 2, wherein T represents agroup C(O)NH.
 5. A compound according to claim 1 or claim 2, wherein nis 2 or
 3. 6. A compound according to claim 1 or claim 2, wherein Xrepresents an oxygen atom or a group C(O) or NH.
 7. A compound accordingto claim 1 or claim 2, wherein R⁴ represents a phenyl group optionallysubstituted by one or two halogen atoms.
 8. A process for thepreparation of a compound of formula (I) as defined in claim 1 whichcomprises (i) when T represents a group C(O)NH, reacting a compound ofgeneral formula

wherein L¹ represents a leaving group and R¹, m and Q are as defined informula (I), with a compound of general formulaR¹—(Q)_(m)—COL¹  (II) or an acid addition salt thereof wherein n, R²,R³, V, W, X and R⁴ are as defined in formula (I); or (ii) when Trepresents a group NH and m is 0, reacting a compound of general formulaR¹-L³  (VI) Wherein L³ represents a leaving group and R¹ is as definedin formula (I), with a compound of formula (III) as defined in (i)above; or (iii) when T represents a group NH, m is I and Q representsC₁-C₄ alkylene, reacting a compound of general formulaR¹—(CH₂)_(p)—CHO  (VII) wherin p is 0, 1, 2 or 3 and R¹ is as definedinformula (I), with a compound of formula (III) as defined in (i) aboveand optionally after (i), (ii), or (iii) converting the compound offormula (I) to a further compound of formula (I) and/or forming apharmaceutically acceptable salt or solvate of the compound of formula(I).
 9. A compound of formula (I), or a pharmaceutically acceptable saltor solvate thereof, according to claim 1 being selected from:N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-furamidehydrochloride,2-[3-}2-[4-(4-Fluorobenzoyl)-1-piperidinyl]ethyl}-2,4-dioxo-3,4-dihydro-1(2H)-quinazolinyl]-N,N-dimethylacetamidehydrochloride,N˜7˜-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-5-methyl[1,3]thiazolo[4,5-d]pyrimidine-2,7-diamine,6-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-2-pyrazinamine,6-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-3-pyridazinamine,6-({2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}amino)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione,3-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-6-methoxy-2,4(1H,3H)-quinazolinedione,N-{2-[4-(3,4-Dichlorophenoxy)-1-pipezidinyl]ethyl}-2-furamide,N-(2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(methylsulfanyl)nicotinamide,N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-thiophenecarboxamide,N-(2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-quinoxalinecarboxamide,2-Chloro-N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}nicotinamide,N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-furamide,N-{2-[4-(4-Chlorobenzoyl)-1-pipendinyl]ethyl}-2-(methylsulfanyl)nicotinamide,N-{2-[4-(4-Chlorobenzoyl)-1-pipendinyl]ethyl}-2-(2,3-dihydro-1,4-benzodioxin-2-yl)-1,3-thiazole-4-carboxamide,N˜2˜-Cyclopropyl-N˜4˜{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-2,4-pyrimidinediamine,2-{[4-({2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}amino)-2-pyrimidinyl]amino}-1-ethanol,2-[[4-({2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}amino)-2-pyrimidinyl](methyl)amino]-1-ethanol,N˜4˜-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-N˜2˜-phenyl-2,4-pyrimidinediamine,N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethy}-2-(methylsulfanyl)-4-pyrimidinamine,N˜4˜-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-N-6-methyl-2,4-pyrimidinediamine,N˜4˜-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-N˜2˜,6-dimethyl-2,4-pyrimidinediamine,2-Chloro-N˜4˜-cyclopropyl-N˜6˜-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-4,6-pyrimidinediamine,N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-[4-phenyl-2-pyrimidinamine,N˜2˜-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-N˜4˜,N˜4˜,6-trimethyl-2,4-pyrimidinediamine,N-{2-[4-(3,4-Dichlorophenoxy)-1-pipendinyl]ethyl}-4-(trifluoromethyl)-2-pyrimidinamine,N-{2-[4-(3,4-Dichlorophenoxy)-1-pipendinyl]ethyl}-4-(propylsulfanyl)-2-pyrimidinamine,N˜2˜-[4-(3,4-Dichlorophenoxy)-1-pipendinyl]ethyl}-N˜4˜-phenyl-2,4-pyrimidinedamine,N˜4˜-Cyclopropyl-N˜2˜-{2-[4-(3,4-dichloraphenoxy)-1-piperidinyl]ethyl}-2,4-pyrimidinamine,N-{2-[4-(3,4-Dichlorophenoxy)-1-pipendinyl]ethyl}-4-(3-pyridinyl)-2-pyrimidinamine,N-{2-[4-(3,4-Dichlorophenoxy)-1-pipendinyl]ethyl}-2-pyrimidinamine,N-{2-[4-(3,4-Dichlorophenoxy)-1-pipendinyl]ethyl}-4,6-dimethoxy-2-pyrimidinamine,N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-(3-furyl)-2-pyrimidinamine,N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-thiophenecarboxamide,N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-quinoxalinecarboxamide,[1-(2-{[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl]amino}ethyl)-4-piperidinyl)(4-chlorophenyl)methanone,(4-Chlorophenyl)[1-(2-{[3-nitro-4-(2-pyridinylsulfanyl)benzyl[amino}ethyl)-4-piperidinyl]methanone,(4-Chlorophenyl){1-[2-({[5-(3-nitrophenyl)-2-furyl]methyl}amino)ethyl)-4-piperidinyl]methanone,(4-Chlorophenyl)[1-(2-{[5-nitro-2-(2-pyridinylsulfanyl)benzyl]amino}ethyl)-4-piperidinyl]methanone,6-[({2-4-(4-Chlorobenzoyl)-1-pipendinyl]ethyl}amino)methyl]-2-(methylsulfanyl)nicotinonitrile,{1-[2-({[5-Chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl}amino)ethyl]-4-piperidinyl}(4-chlorophenyl)methanone,(4-Chlorophenyl)[1-(2-{[(4-phenyl-4-piperidinyl)methy]amino}ethyl)-4-piperidinyl]methanone,(4-Chlorophenyl)[1-(2-{[(1-phenyl-1H-pyrazol-5-yl)methyl]amino}ethyl)-4-piperidinyl]methanone,(4-Chlorophenyl)(1-{2-[(2-pyridinylmethyl)amino]ethyl}-4-piperidinyl)methanone,(4-Chlorophenyl)[1-(2-{[(3-methyl-2-thienyl)methyl]amino}ethyl)-4-piperidinyl]methanone,[1-(2-{[5-Chloro-1,3-dimethyl-1H-pyrazol-[4-yl)methyl]amino}ethyl)-4-piperidinyl](4-chlorophenyl]methanone,(4-Chlorophenyl)[1-(2-{[(2,6-dichloro-4-pyridinyl)methyl]amino}ethyl)-4-piperidinyl]methanone,(4-Chlorophenyl)[1-(2-{[(2-phenyl-1H-imidazol-4-yl)methyl]amino}ethyl)-4-piperidinyl]methanone,(4-Chlorophenyl)[1-(2-{[(5-ethyl-2-thienyl)methyl]amino}ethyl)-4-piperidinyl]methanone,(4-Chlorophenyl)[1-(2-{[(2-chloro-3-quinolinyl)methyl]ammo}ethyl)-4-piperidinyl]methanone,(4-Chlorophenyl)[1-(2-{[(6-methyl-2-pyridinyl)methyl]amino}ethyl)-4-piperidinyl]methanone,(4-Chlorophonyl)(1-{2-[(3-quinolinylmethyl)amino[ethyl}-4-piperidinyl)methanone,4-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}amino)methyl]-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one,(4-Chlorophenyl)(1-{2-[(4-pyridinylmethyl)amino]ethyl}-4-piperidinyl)methanone,[1-(2-{[(4-Bromo-1H-pyrazol-3-yl)methyl]amino}ethyl)-4-piperidinyl](4-chlorophenyl)methanone,(4-Chlorophenyl)[1-(2-{[(2,4-dimethoxy-5-pyrimidinyl)methyl]amino}ethyl)-4-piperidinyl]methanone,5-Bromo-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-2-furamide,N-{2-[4-(3,4-Dichlorophenoxy)-1-pipendinyl]ethyl}-3-methyl-2-furamide,N-{2-[4-(3,4-Dichlorophenoxy)-1-pipendinyl]ethyl}-4,5-dimetyl-2-furamide,2-Amino-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-1,3-thiazole-4-carboxamide,2-Acetylamino)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-1,3-thiazole-4-carboxamide,N-{2-[4-(3,4-Dichlorophenoxy)-1-pipendinyl]ethyl}-2-(4-pyridinyl)-1,3-thiazole-4-carboxamide,N-{2-[4-(3,4-Dichlorophenoxy)-1-pipendinyl]ethyl}-2,4-dimethyl-1,3-thiazole-5-carbaxamide,N-{2-[4-(3,4-Dichlorophenoxy)-1-pipendinyl]ethyl}-2,5-dimethyl-1,3-oxazole-4-carboxamide,N-{2-[4-(3,4-Dichlorophenoxy)-1-pipendinyl]ethyl}-1H-imidazole-4-carboxamide,N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2,6-dimethoxy-4-pyrimidinamine,N˜4˜-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-N˜2˜,N˜-2˜dimethyl-2,4-pyrimidinediamine,N-(3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-[(methylsulfanyl)methyl]-4-pyrimidinamine,N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-(methylsulfanyl)-6-(trifluoromethyl)-4-pyrimidinamine,N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-5-methoxy-2-(methylsulfanyl)-4-pyrimidinamine,N-{3-[4-(3,4-Diohlorophenoxy)-1-piperidinyl]ropyl}-6-methyl-2-(methylsulfanyl)-4-pyrimidinamine,N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-5-methoxy-2-methyl-4-pyrimidinamine,N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-(ethylsulfanyl)-6-methyl-4-pyrimidinamine,N˜2˜-Cyclopropyl-N˜4˜-}3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]propyl}-2,4-pyrimidinediamine,2-{[4-({3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}amino)-2-pyrimidinyl]amino}-1-ethanol,2-[[4-({3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}amino)-2-pyrimidinyl](methyl)amino]-1-ethanol,N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-(methylsulfanyl)-4-pyrimidinamine,N˜4˜-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-6-methyl-2,4-pyrimidinamine,N˜4˜-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-N˜2˜,6-dimethyl-2,4-pyrimidinamine,N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-phenyl-2-pyrimidinamine,N˜2˜-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-5-fluoro-2,4-pyrimidinediamine,N˜2˜-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-N˜4˜,N˜4˜,6-trimethyl-2,4-pyrimidinediamine,N-}3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-[4-(trifluoromethyl)-2-pyrimidinediamine,N-}3-[4-(3,4-Dichorophenoxy)-1-piperidinyl]propyl}-4-(propylsulfanyl)-2-pyrimidinediamine,N˜2˜-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-N˜4˜-phenyl-2,4-pyrimidinediamine,N˜2˜-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-N˜4˜,6-dimethyl-2,4-pyrimidinediamine,2-{[2-({3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}amino)-4-pyrimidinyl]amino}-1-ethanol,2-[[2-({3-[4-(3,4-Dichlorophenoxy)-1-pipendinyl]propyl}amino)-4-pyrimidinyl](methyl)amino]-1-ethanol,N-}3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-(3-pyridinyl)-2-pyrimidinamine,N-}3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-(3-thienyl)-2-pyrimidinamine,N-}3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-pyrimidinamine,N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4,6-dimethoxy-2-pyrimidinamine,N-}3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]piopyl}-4-(3-furyl)-2-pyrimidinamine,N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-(2-thienyl)-2-pyrimidinamine,N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-pyridinamine,5-Chloro-N-{3-[4-(3,4-dichlorophenaxy)-1-piperidinyl]propyl}-2-pyridinamine,6-Chloro-N-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]propyl}-2-pyridinamine,N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-6-methyl-2-pyridinamine,6-Chloro-N-}3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]propyl}-2-pyrazinamine,6-Chloro-N-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]propyl}-3-pyrdazinamine,6-({3-(4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}amino)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione,N-{2-4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2,6-dimethoxy-4-pyrimidinamine,N˜4˜-}2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-N˜2˜,N˜2˜-dimethyl-2,4-pyrimidinediamine,N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-[(methylsulfanyl)methyl]-4-pyrimidinamine,N-(2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-5-methoxy-2-(methylsulfanyl)-4-pyrimidinamine,N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-6-methyl-2-(methylsulfanyl)-4-pyrimidinamine,N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-5-methoxy-2-methyl-4-pyrimidinamine,andN˜4˜-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-6-methyl-N˜2˜-phenyl-2,4-pyrimidinediamine.10. A pharmaceutical composition comprising a compound of formula (I),or a pharmaceutically acceptable salt or solvate thereof; as claimed inclaim 1 or claim 9 in association with a pharmaceutically acceptableadjuvant, diluent or carrier.
 11. A process for the preparation of apharmaceutical composition as claimed in claim 10 which comprises mixinga compound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as claimed in claim 1 or claim 9 with apharmaceutically acceptable adjuvant, diluent or carrier.
 12. Theprocess of claim 8 wherein L₁ is a hydroxyl group.
 13. The process ofclaim 8 whercin L₁ is halide group.
 14. The process of claim 8 whereinsaid addition salt of formula (III) is trifluoroacetate.
 15. The processof claim 8 wherein L₃ is halogen atom.